The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer

The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed.

[1]  J. Grandis,et al.  STAT3 signaling: anticancer strategies and challenges. , 2011, Molecular interventions.

[2]  Lin Qiu,et al.  Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth. , 2005, Cancer research.

[3]  Hua Yu,et al.  Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. , 2014, Cancer research.

[4]  M. Amling,et al.  Osteolytic prostate cancer cells induce the expression of specific cytokines in bone-forming osteoblasts through a Stat3/5-dependent mechanism. , 2010, Bone.

[5]  J. Simons,et al.  Interleukin-6: a candidate mediator of human prostate cancer morbidity. , 1995, Urology.

[6]  I. Díaz-Laviada.  Effect of capsaicin on prostate cancer cells. , 2010, Future oncology.

[7]  M. Marques,et al.  New strategies against prostate cancer--Pt(II)-based chemotherapy. , 2012, Current medicinal chemistry.

[8]  P. Dobrzanski,et al.  Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-Induced Colorectal Cancer , 2012, Molecular Cancer Therapeutics.

[9]  M. Rubin,et al.  Genomic rearrangements in prostate cancer , 2015, Current opinion in urology.

[10]  C. Eaves,et al.  Targeting YB-1 in HER-2 overexpressing breast cancer cells induces apoptosis via the mTOR/STAT3 pathway and suppresses tumor growth in mice. , 2008, Cancer research.

[11]  H. Hong,et al.  Plumbagin, a medicinal plant (lumbago zeylanica)‐derived 1,4‐naphthoquinone, inhibits growth and metastasis of human prostate cancer PC‐3M‐luciferase cells in an orthotopic xenograft mouse model , 2013, Molecular oncology.

[12]  A. Giobbie-Hurder,et al.  The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition , 2012, Clinical Cancer Research.

[13]  Aaron R Cooper,et al.  Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells , 2013, Proceedings of the National Academy of Sciences.

[14]  F. Sarkar,et al.  A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. , 2010, American journal of translational research.

[15]  J. T. Sanderson,et al.  Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells. , 2013, Bioorganic & medicinal chemistry.

[16]  Tong Zhang,et al.  Protein Kinase C δ Associates with and Phosphorylates Stat3 in an Interleukin-6-dependent Manner* , 1999, The Journal of Biological Chemistry.

[17]  G. Fraizer,et al.  Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site , 2013, Molecular Cancer.

[18]  Ravi Iyengar,et al.  G protein coupled receptor signaling through the Src and Stat3 pathway: role in proliferation and transformation , 2001, Oncogene.

[19]  Chawnshang Chang,et al.  Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling. , 2013, Cancer research.

[20]  Mozaffarul Islam,et al.  RhoC Regulates Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma by Overexpressing IL-6 and Phosphorylation of STAT3 , 2014, PloS one.

[21]  Z. Estrov,et al.  Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells. , 2007, Leukemia research.

[22]  J. Wood,et al.  Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia , 2011, Blood cancer journal.

[23]  H. Klocker,et al.  Hyperactive androgen receptor in prostate cancer: what does it mean for new therapy concepts? , 1997, Histology and histopathology.

[24]  Z. Estrov,et al.  Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor , 2011, Investigational New Drugs.

[25]  K. Jennbacken,et al.  N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. , 2010, Endocrine-related cancer.

[26]  Patricia D. Castro,et al.  Celastrol Suppresses Tumor Cell Growth through Targeting an AR-ERG-NF-κB Pathway in TMPRSS2/ERG Fusion Gene Expressing Prostate Cancer , 2013, PloS one.

[27]  Martin R. Schneider,et al.  Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system , 1999, British Journal of Cancer.

[28]  Syed Tarique Moin,et al.  Dynamic changes in the secondary structure of ECE-1 and XCE account for their different substrate specificities , 2012, BMC Bioinformatics.

[29]  K. Heeg,et al.  PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3 , 2011, European journal of immunology.

[30]  S. Akira,et al.  IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages , 2003, Nature Immunology.

[31]  N. Jing,et al.  Combined treatment targeting HIF‐1α and Stat3 is a potent strategy for prostate cancer therapy , 2011, The Prostate.

[32]  Wenzheng Zhang,et al.  Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. , 2002, The Biochemical journal.

[33]  J. Turkson,et al.  Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Nam‐Hoon Kim,et al.  Auranofin blocks interleukin‐6 signalling by inhibiting phosphorylation of JAK1 and STAT3 , 2007, Immunology.

[35]  R. Jove,et al.  Sorafenib Induces Growth Arrest and Apoptosis of Human Glioblastoma Cells through the Dephosphorylation of Signal Transducers and Activators of Transcription 3 , 2010, Molecular Cancer Therapeutics.

[36]  G. Stark,et al.  Roles of unphosphorylated STATs in signaling , 2008, Cell Research.

[37]  T. Sugino,et al.  Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression. , 2013, European journal of cancer.

[38]  Lie-Chwen Lin,et al.  Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP , 2004, International journal of cancer.

[39]  N. Jing,et al.  Targeting Stat3 with G-quartet oligodeoxynucleotides in human cancer cells. , 2003, DNA and cell biology.

[40]  W. Dougall,et al.  RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes , 2008, The Prostate.

[41]  M. Moore,et al.  Genomic Rearrangements of PTEN in Prostate Cancer , 2013, Front. Oncol..

[42]  M. Wicha,et al.  Evaluation of STAT3 Signaling in ALDH+ and ALDH+/CD44+/CD24− Subpopulations of Breast Cancer Cells , 2013, PloS one.

[43]  Mei Zhao,et al.  JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer. , 2011, Lung cancer.

[44]  Simion I. Chiosea,et al.  First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. , 2012, Cancer discovery.

[45]  S. Serrano,et al.  Lestaurtinib Inhibition of the JAK/STAT Signaling Pathway in Hodgkin Lymphoma Inhibits Proliferation and Induces Apoptosis , 2011, PloS one.

[46]  Xinmin Cao,et al.  Serine Phosphorylation and Negative Regulation of Stat3 by JNK* , 1999, The Journal of Biological Chemistry.

[47]  C. Burns,et al.  The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells , 2011, Leukemia.

[48]  C. Teng,et al.  Induction of mitotic arrest and apoptosis in human prostate cancer pc-3 cells by evodiamine. , 2005, The Journal of urology.

[49]  B. Dörken,et al.  In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway. , 2002, Blood.

[50]  Nam‐Hoon Kim,et al.  Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells , 2013, BMB reports.

[51]  M. Gleave,et al.  Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis. , 2005, Cancer research.

[52]  M. Azam,et al.  Overcoming AC220 resistance of FLT3-ITD by SAR302503 , 2013, Blood Cancer Journal.

[53]  E. Hurt,et al.  Effects of the sesquiterpene lactone parthenolide on prostate tumor‐initiating cells: An integrated molecular profiling approach , 2009, The Prostate.

[54]  Qiang Z Yu,et al.  Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. , 2013, Cancer letters.

[55]  B. Cochran,et al.  Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells , 2003, BMC Cancer.

[56]  M. Hance,et al.  Extracellular Hsp90 mediates an NF‐κB dependent inflammatory stromal program: Implications for the prostate tumor microenvironment , 2014, The Prostate.

[57]  Pui-Kai Li,et al.  Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. , 2010, Cancer research.

[58]  Sarat Chandarlapaty,et al.  Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. , 2011, Cancer cell.

[59]  W. Ye,et al.  CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. , 2012, Cancer research.

[60]  Howard Colman,et al.  Quantitative phosphoproteomic analysis of the STAT3/IL-6/HIF1alpha signaling network: an initial study in GSC11 glioblastoma stem cells. , 2010, Journal of proteome research.

[61]  F. Gao,et al.  Small molecule inhibitors of STAT3 for cancer therapy. , 2011, Current medicinal chemistry.

[62]  Yihui Deng,et al.  Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. , 2010, European journal of pharmacology.

[63]  D. Kalvakolanu,et al.  Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment , 2013, Journal of Cancer Research and Clinical Oncology.

[64]  Miao-Fen Chen,et al.  The role of IL-6 in the radiation response of prostate cancer , 2013, Radiation oncology.

[65]  W. Zhong,et al.  Plumbagin inhibits prostate cancer development in TRAMP mice via targeting PKCε, Stat3 and neuroendocrine markers. , 2012, Carcinogenesis.

[66]  Payam Shahi,et al.  FGFR1-WNT-TGF-β signaling in prostate cancer mouse models recapitulates human reactive stroma. , 2014, Cancer research.

[67]  K. Pienta,et al.  Disseminated Prostate Cancer Cells Can Instruct Hematopoietic Stem and Progenitor Cells to Regulate Bone Phenotype , 2012, Molecular Cancer Research.

[68]  F. Meneghetti,et al.  Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy. , 2011, Future medicinal chemistry.

[69]  B. Le Goff,et al.  DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. , 2007, Bone.

[70]  L. Kvols,et al.  Phase II proof-of-concept study of atiprimod in patients with advanced low- to intermediate-grade neuroendocrine carcinoma , 2008 .

[71]  Li Lin,et al.  XZH-5 Inhibits STAT3 Phosphorylation and Enhances the Cytotoxicity of Chemotherapeutic Drugs in Human Breast and Pancreatic Cancer Cells , 2012, PloS one.

[72]  H. Klocker,et al.  Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[73]  E. Keller,et al.  Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[74]  J. Turkson,et al.  Requirement for Ras/Rac1-Mediated p38 and c-Jun N-Terminal Kinase Signaling in Stat3 Transcriptional Activity Induced by the Src Oncoprotein , 1999, Molecular and Cellular Biology.

[75]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[76]  K. Jeong,et al.  A ROS/STAT3/HIF‐1α signaling cascade mediates EGF‐induced TWIST1 expression and prostate cancer cell invasion , 2014, The Prostate.

[77]  J. Karras,et al.  Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. , 2004, Molecular cancer therapeutics.

[78]  Chawnshang Chang,et al.  Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis* , 2012, The Journal of Biological Chemistry.

[79]  Tobias Rumpf,et al.  Lestaurtinib Inhibits Histone Phosphorylation and Androgen-Dependent Gene Expression in Prostate Cancer Cells , 2012, PloS one.

[80]  S. Machida,et al.  Interleukin‐6‐induced satellite cell proliferation is regulated by induction of the JAK2/STAT3 signalling pathway through cyclin D1 targeting , 2013, Cell proliferation.

[81]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[82]  R. M. Simpson,et al.  Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition. , 2011, The American journal of pathology.

[83]  S. Yeh,et al.  New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells. , 2013, Journal of molecular cell biology.

[84]  B. Leiby,et al.  Pharmacologic Inhibition of Jak2–Stat5 Signaling By Jak2 Inhibitor AZD1480 Potently Suppresses Growth of Both Primary and Castrate-Resistant Prostate Cancer , 2013, Clinical Cancer Research.

[85]  K. Jeong,et al.  STAT3 mediates TGF-β1-induced TWIST1 expression and prostate cancer invasion. , 2013, Cancer letters.

[86]  D. Hanahan,et al.  Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. , 1999, Cancer research.

[87]  N. Jing,et al.  G-Quartet Oligonucleotides , 2004, Cancer Research.

[88]  Z. Ye,et al.  Curcumin induces cell cycle arrest and apoptosis of prostate cancer cells by regulating the expression of IkappaBalpha, c-Jun and androgen receptor. , 2013, Die Pharmazie.

[89]  H. Gascan,et al.  Functional Interaction of STAT3 Transcription Factor with the Coactivator NcoA/SRC1a* , 2002, The Journal of Biological Chemistry.

[90]  A. Bjartell,et al.  Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer , 2013, Oncogene.

[91]  M. Gleave,et al.  Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. , 2013, Cancer research.

[92]  L. Ellis,et al.  Class I Histone Deacetylase Inhibitor Entinostat Suppresses Regulatory T Cells and Enhances Immunotherapies in Renal and Prostate Cancer Models , 2012, PloS one.

[93]  J. T. Sanderson,et al.  Proliferative and androgenic effects of indirubin derivatives in LNCaP human prostate cancer cells at sub-apoptotic concentrations. , 2011, Chemico-biological interactions.

[94]  Y. Kwon,et al.  Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. , 2013, Cellular signalling.

[95]  A. Rathinavelu,et al.  A novel regulation of VEGF expression by HIF-1α and STAT3 in HDM2 transfected prostate cancer cells , 2012, Journal of cellular and molecular medicine.

[96]  L. Chung,et al.  PrLZ protects prostate cancer cells from apoptosis induced by androgen deprivation via the activation of Stat3/Bcl-2 pathway. , 2011, Cancer research.

[97]  Bao-xue Yang,et al.  Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo. , 2011, Asian journal of andrology.

[98]  S. Safe,et al.  Ring-substituted analogs of 3,3′-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and –independent prostate cancer cells , 2014, Investigational New Drugs.

[99]  Jiaoti Huang,et al.  The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. , 2012, Cell stem cell.

[100]  J. Abbruzzese,et al.  Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis , 2003, Oncogene.

[101]  X. Wang,et al.  Clinical implications of cancer stem cell biology in hepatocellular carcinoma. , 2012, Seminars in oncology.

[102]  M. Aziz,et al.  Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. , 2008, Cancer research.

[103]  STAT3: A critical transcription activator in angiogenesis , 2008, Medicinal research reviews.

[104]  E. Batlle,et al.  TGF-beta in CAF-mediated tumor growth and metastasis. , 2014, Seminars in cancer biology.

[105]  Renxiao Wang,et al.  A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[106]  D. Heymann,et al.  Receptor activator of nuclear factor-kappa B ligand (RANKL) stimulates bone-associated tumors through functional RANK expressed on bone-associated cancer cells? , 2009, Histology and histopathology.

[107]  J. Luk,et al.  Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo , 2012, Cancer Prevention Research.

[108]  D. Tindall,et al.  p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. , 2005, Cancer research.

[109]  Xia Li,et al.  A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma. , 2014, Carcinogenesis.

[110]  D. Amadori,et al.  Pathogenesis of osteoblastic bone metastases from prostate cancer , 2010, Cancer.

[111]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[112]  S. Yeh,et al.  Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling , 2013, Cell Death and Disease.

[113]  Wei-Chiao Chang,et al.  Molecular Sciences Protective Effect of Caffeic Acid on Paclitaxel Induced Anti-proliferation and Apoptosis of Lung Cancer Cells Involves Nf-κb Pathway , 2022 .

[114]  C. Evans,et al.  NF-κB2/p52 Induces Resistance to Enzalutamide in Prostate Cancer: Role of Androgen Receptor and Its Variants , 2013, Molecular Cancer Therapeutics.

[115]  W. Guida,et al.  A novel inhibitor of STAT3 homodimerization selectively suppresses STAT3 activity and malignant transformation. , 2013, Cancer research.

[116]  Corinne M. Silva.  Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis , 2004, Oncogene.

[117]  C. Evans,et al.  MP24-07 NF-KAPPAB2/P52 INDUCES RESISTANCE TO ENZALUTAMIDE IN PROSTATE CANCER: ROLE OF ANDROGEN RECEPTOR AND ITS VARIANTS , 2014 .

[118]  R. Lai,et al.  Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. , 2006, Blood.

[119]  P. Yue,et al.  Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts , 2012, Proceedings of the National Academy of Sciences.

[120]  G. Ciliberto,et al.  Blocking signaling through the gp130 receptor chain by interleukin‐6 and oncostatin M inhibits PC‐3 cell growth and sensitizes the tumor cells to etoposide and cisplatin‐mediated cytotoxicity , 1999, Cancer.

[121]  R. Ray,et al.  Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling , 2008, Journal of Virology.

[122]  P. Ross-Macdonald,et al.  Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2 , 2012, Leukemia.

[123]  Takuya Matsunaga,et al.  R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm. , 2011, Blood.

[124]  M. Kortylewski,et al.  Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. , 2014, Blood.

[125]  Hong Wang,et al.  Novel small molecule, XZH‐5, inhibits constitutive and interleukin‐6‐induced STAT3 phosphorylation in human rhabdomyosarcoma cells , 2011, Cancer science.

[126]  M. Kizaki,et al.  Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor , 2007, Molecular Cancer Therapeutics.

[127]  Tatsuo Kanda,et al.  Involvement of interleukin-6 and androgen receptor signaling in pancreatic cancer. , 2010, Genes & cancer.

[128]  D. Trump,et al.  RNA interference targeting Stat3 inhibits growth and induces apoptosis of human prostate cancer cells , 2004, The Prostate.

[129]  Rolf Rossaint,et al.  Activation of STAT3 by IL-6 and IL-10 in Primary Human Macrophages Is Differentially Modulated by Suppressor of Cytokine Signaling 3 1 , 2003, The Journal of Immunology.

[130]  Li Lin,et al.  A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. , 2010, Neoplasia.

[131]  Yi Lu,et al.  Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. , 2006, Cancer research.

[132]  M. Russo,et al.  Cell-to-Cell Signaling Influences the Fate of Prostate Cancer Stem Cells and Their Potential to Generate More Aggressive Tumors , 2012, PloS one.

[133]  R. Vessella,et al.  Histopathological assessment of prostate cancer bone osteoblastic metastases. , 2008, The Journal of urology.

[134]  J. Blando,et al.  Cooperation between Stat3 and Akt signaling leads to prostate tumor development in transgenic mice. , 2011, Neoplasia.

[135]  Hua Yu,et al.  TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. , 2013, Blood.

[136]  Georg Breier,et al.  Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo , 1992, Nature.

[137]  Y. Lou,et al.  Hypoxia preconditioning of mesenchymal stromal cells enhances PC3 cell lymphatic metastasis accompanied by VEGFR‐3/CCR7 activation , 2013, Journal of cellular biochemistry.

[138]  L. Ellis,et al.  HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas , 2005, Oncogene.

[139]  J. Isaacs,et al.  Mesenchymal stem cells as a vector for the inflammatory prostate microenvironment. , 2013, Endocrine-related cancer.

[140]  Susan Halabi,et al.  Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[141]  J. Avruch,et al.  Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR , 2000, Current Biology.

[142]  T. D. de Reijke,et al.  New developments in castrate‐resistant prostate cancer , 2012, BJU international.

[143]  N. Bruchovsky,et al.  Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways* , 2002, The Journal of Biological Chemistry.

[144]  E. Haura,et al.  JAK1 Activates STAT3 Activity in Non-Small–Cell Lung Cancer Cells and IL-6 Neutralizing Antibodies Can Suppress JAK1-STAT3 Signaling , 2011, Molecular Cancer Therapeutics.

[145]  X. Tian,et al.  JAK-STAT3 and somatic cell reprogramming , 2013, JAK-STAT.

[146]  T. Mustelin,et al.  Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[147]  P. Dobrzanski,et al.  A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis , 2011, Arthritis research & therapy.

[148]  J. Blenis,et al.  STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation , 1997, Molecular and cellular biology.

[149]  R. Weinberg,et al.  Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. , 2012, Seminars in cancer biology.

[150]  Jing Ma,et al.  Regulation of Stat3 nuclear import by importin α5 and importin α7 via two different functional sequence elements , 2006 .

[151]  K. Kuroiwa,et al.  YB-1 suppression induces STAT3 proteolysis and sensitizes renal cancer to interferon-α , 2013, Cancer Immunology, Immunotherapy.

[152]  S. Yeh,et al.  Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. , 2012, Cancer letters.

[153]  M. Gleave,et al.  The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer , 2013, Current opinion in urology.

[154]  Chawnshang Chang,et al.  Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation , 2013, EMBO molecular medicine.

[155]  J. Canon,et al.  RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis , 2008, Molecular Cancer Therapeutics.

[156]  N. Maitland,et al.  JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. , 2013, Cancer research.

[157]  S. Yamasaki,et al.  Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production , 2011, BMC Immunology.

[158]  N. Varin‐Blank,et al.  A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line , 2012, Molecular Cancer.

[159]  Soo-Jin Jeong,et al.  Suppression of STAT3 and HIF-1 Alpha Mediates Anti-Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells , 2011, PloS one.

[160]  H. Park,et al.  Capsaicin inhibits the IL-6/STAT3 pathway by depleting intracellular gp130 pools through endoplasmic reticulum stress. , 2009, Biochemical and biophysical research communications.

[161]  M. Kronenberg,et al.  HVEM: An unusual TNF receptor family member important for mucosal innate immune responses to microbes. , 2013, Gut microbes.

[162]  P. Möller,et al.  NF-κB signaling in prostate cancer: A promising therapeutic target? , 2012, World Journal of Urology.

[163]  S. Safe,et al.  Antiandrogenic and growth inhibitory effects of ring‐substituted analogs of 3,3′‐diindolylmethane (Ring‐DIMs) in hormone‐responsive LNCaP human prostate cancer cells , 2011, The Prostate.

[164]  Jennifer L. Mason,et al.  A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. , 2012, Journal of medicinal chemistry.

[165]  Bianca Sperl,et al.  Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. , 2006, Chemistry & biology.

[166]  Olov Sterner,et al.  Galiellalactone is a novel therapeutic candidate against hormone‐refractory prostate cancer expressing activated Stat3 , 2008, The Prostate.

[167]  M. Karin,et al.  Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. , 2010, Cytokine & growth factor reviews.

[168]  Prabodh K. Kandala,et al.  Regulation of Janus-activated kinase-2 (JAK2) by diindolylmethane in ovarian cancer in vitro and in vivo. , 2012, Drug discoveries & therapeutics.

[169]  E. Sausville,et al.  Cucurbitacin E-induced disruption of the actin and vimentin cytoskeleton in prostate carcinoma cells. , 1996, Biochemical pharmacology.

[170]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[171]  K. Kuroiwa,et al.  Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression. , 2011, Endocrine-related cancer.

[172]  Bulbul Pandit,et al.  Design, synthesis, and studies of small molecule STAT3 inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[173]  David E. Williams,et al.  Effects of Sulforaphane and 3,3′-Diindolylmethane on Genome-Wide Promoter Methylation in Normal Prostate Epithelial Cells and Prostate Cancer Cells , 2014, PloS one.

[174]  Hua Yu,et al.  Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. , 2009, Cancer cell.

[175]  Zigang Dong,et al.  Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2. , 2012, Carcinogenesis.

[176]  G. Sethi,et al.  Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. , 2013, Biochimica et biophysica acta.

[177]  D. Rowley,et al.  The reactive stroma microenvironment and prostate cancer progression. , 2012, Endocrine-related cancer.

[178]  Mingyao Liu,et al.  Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2‐mediated JAK/STAT3 signaling in endothelial cell , 2011, International journal of cancer.

[179]  C. Drake,et al.  Combining immunological and androgen-directed approaches: an emerging concept in prostate cancer immunotherapy , 2012, Current opinion in oncology.

[180]  R. Levine,et al.  LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells , 2008, Molecular Cancer Therapeutics.

[181]  J. Rhim,et al.  Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines. , 2002, International journal of oncology.

[182]  M. Henry,et al.  Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? , 2011, Nature Reviews Urology.

[183]  Jing Ma,et al.  Regulation of Stat3 nuclear import by importin alpha5 and importin alpha7 via two different functional sequence elements. , 2006, Cellular signalling.

[184]  S. Hayward,et al.  Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis , 2008, Oncogene.

[185]  Jean Paul Thiery,et al.  Epithelial-mesenchymal transitions: insights from development , 2012, Development.

[186]  D. Han,et al.  Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. , 2009, Cancer research.

[187]  Hua Yu,et al.  Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. , 2008, The Journal of clinical investigation.

[188]  T. Chung,et al.  STAT3 mediates IL‐6‐induced neuroendocrine differentiation in prostate cancer cells , 2000, The Prostate.

[189]  A. Thomson,et al.  IL-27 Production and STAT3-Dependent Upregulation of B7-H1 Mediate Immune Regulatory Functions of Liver Plasmacytoid Dendritic Cells , 2012, The Journal of Immunology.

[190]  B. Bao,et al.  Inactivation of AR/TMPRSS2-ERG/Wnt Signaling Networks Attenuates the Aggressive Behavior of Prostate Cancer Cells , 2011, Cancer Prevention Research.

[191]  R. Dhir,et al.  Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak , 2005, Molecular Cancer Therapeutics.

[192]  M. Kattan,et al.  Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. , 1999, The Journal of urology.

[193]  E. Keller,et al.  Anti‐interleukin‐6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice , 2001, The Prostate.

[194]  Hua Yu,et al.  The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. , 2009, Cancer cell.

[195]  O. Witte,et al.  Interleukin-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway to Promote Aggressive Prostate Malignancy in Mouse and Human Tissues , 2013, Molecular Cancer Research.

[196]  J. Turkson,et al.  Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. , 2004, Molecular cancer therapeutics.

[197]  Y. Horiguchi,et al.  Serum interleukin 6 as a prognostic factor in patients with prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[198]  Zhiwei Wang,et al.  Epithelial to Mesenchymal Transition Is Mechanistically Linked with Stem Cell Signatures in Prostate Cancer Cells , 2010, PloS one.

[199]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[200]  W. Reichelt,et al.  Comparison of gene expression in HCT116 treatment derivatives generated by two different 5-fluorouracil exposure protocols , 2004, Molecular Cancer.

[201]  W. Guida,et al.  Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity , 2007, Proceedings of the National Academy of Sciences.

[202]  S. Akyol,et al.  The anticancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. , 2012, European review for medical and pharmacological sciences.

[203]  Z. Estrov,et al.  Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells , 2005, British Journal of Cancer.

[204]  Yezi Zhu,et al.  Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells , 2014, The Prostate.

[205]  R. Gude,et al.  Role of STAT3 in Cancer Metastasis and Translational Advances , 2013, BioMed research international.

[206]  Yuzhuo Wang,et al.  Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage. , 2013, Carcinogenesis.

[207]  M. Karin,et al.  B-cell-derived lymphotoxin promotes castration-resistant prostate cancer , 2010, Nature.

[208]  K. Kalland,et al.  Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. , 2013, Cancer research.

[209]  J. Bono,et al.  Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. , 2012, European journal of cancer.

[210]  J. Settleman,et al.  EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer , 2010, Oncogene.

[211]  Qiuyang Zhang,et al.  LNCaP prostate cancer cells with autocrine interleukin‐6 expression are resistant to IL‐6‐induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling , 2012, The Prostate.

[212]  Hideaki Mizuno,et al.  Molecular classification of prostate cancer using curated expression signatures , 2011, Proceedings of the National Academy of Sciences.

[213]  Y. Whang,et al.  A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer , 2013, Investigational New Drugs.

[214]  G. Semenza,et al.  Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways , 2005, Oncogene.

[215]  D. Frank,et al.  Microtubule-Targeted Chemotherapeutic Agents Inhibit Signal Transducer and Activator of Transcription 3 (STAT3) Signaling , 2010, Molecular Pharmacology.

[216]  M. Seibel,et al.  Mechanisms of Disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis , 2006, Nature Clinical Practice Oncology.

[217]  Randy S. Schrecengost,et al.  Molecular pathogenesis and progression of prostate cancer. , 2013, Seminars in oncology.

[218]  Xiaobai Liu,et al.  Curcumin Blocks Small Cell Lung Cancer Cells Migration, Invasion, Angiogenesis, Cell Cycle and Neoplasia through Janus Kinase-STAT3 Signalling Pathway , 2012, PloS one.

[219]  Delong Liu,et al.  Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application , 2013, Biomarker Research.

[220]  O. Smaletz,et al.  Castration-resistant prostate cancer: systemic therapy in 2012 , 2012, Clinics.