Interleukin-6 and prostate cancer progression.

Prostate cancer, while initially dependent on androgens for proliferation, progresses to an androgen-independent state. Evidence has been accumulating that interleukin-6 (IL-6) may contribute to prostate cancer progression. Serum levels of IL-6 correlate with prostate tumor burden and patient morbidity. The prostate tissue itself appears to be a source of IL-6 and its receptor. Furthermore, experimental data suggest that IL-6 is an autocrine and paracrine growth factor for androgen-independent prostate cancer cell lines. For example, inhibition of IL-6, with anti-IL-6 antibody, sensitizes androgen-independent prostate cancer cells to chemotherapeutic agents in vitro. Finally, IL-6 activates a variety of signal transduction cascades, some which stimulate androgen receptor activity, in prostate cancer cells. These data suggest that targeting IL-6 may have multiple benefits in prostate cancer patients.

[1]  E. Keller,et al.  Molecular and cellular biology of interleukin-6 and its receptor. , 1996, Frontiers in bioscience : a journal and virtual library.

[2]  T. Hirano,et al.  Molecular cloning and expression of an IL-6 signal transducer, gp130 , 1990, Cell.

[3]  P. Heinrich,et al.  Soluble receptors for cytokines and growth factors: generation and biological function. , 1994, The Biochemical journal.

[4]  G. Murphy,et al.  Circulating levels of interleukin‐6 in patients with hormone refractory prostate cancer , 1999, The Prostate.

[5]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[6]  D. Tindall,et al.  The effects of growth factors associated with osteoblasts on prostate carcinoma proliferation and chemotaxis: implications for the development of metastatic disease. , 1997, Endocrinology.

[7]  P. Walsh,et al.  Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy , 1991, Cancer.

[8]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

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

[10]  C. Logothetis,et al.  Clinical significance of elevation in neuroendocrine factors and interleukin-6 in metastatic prostate cancer. , 1995, Urologic oncology.

[11]  F. Fauvel-Lafève,et al.  Stromal cells from human benign prostate hyperplasia produce a growth‐inhibitory factor for LNCaP prostate cancer cells, identified as interleukin‐6 , 1996, International journal of cancer.

[12]  W. Rosner,et al.  Estradiol Activates the Prostate Androgen Receptor and Prostate-specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin* , 1997, The Journal of Biological Chemistry.

[13]  P. Koistinen,et al.  Acute myeloblastic leukaemia cells produce soluble interleukin 6 receptor by a mechanism of alternative splicing. , 1998, Cytokine.

[14]  T. Taniguchi Cytokine signaling through nonreceptor protein tyrosine kinases. , 1995, Science.

[15]  H. Klocker,et al.  Androgen receptor status of lymph node metastases from prostate cancer , 1996, The Prostate.

[16]  R. Kyle,et al.  Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. , 1992, Cytokine.

[17]  H. Broxmeyer,et al.  Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. , 1995, The Journal of clinical investigation.

[18]  Y. Yang,et al.  Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells. , 1994, The Journal of biological chemistry.

[19]  T. Taniguchi,et al.  Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. , 1988, Science.

[20]  Noah Craft,et al.  A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase , 1999, Nature Medicine.

[21]  P. Heinrich,et al.  Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. , 1992, Journal of immunology.

[22]  S. Tóth,et al.  Generation of 'truncated' interleukin-6 receptor (IL-6R) mRNA by alternative splicing; a possible source of soluble IL-6R. , 1999, Immunology letters.

[23]  P. Pelicci,et al.  Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. , 1997, Journal of immunology.

[24]  D. Peehl,et al.  1α,25-Dihydroxyvitamin D3 Actions in LNCaP Human Prostate Cancer Cells Are Androgen-Dependent. , 1997, Endocrinology.

[25]  T. Hirano The biology of interleukin-6. , 1992, Chemical immunology.

[26]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[27]  T. Hirano,et al.  Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. , 1996, Immunity.

[28]  B. Bonavida,et al.  Dexamethasone enhances expression of membrane and soluble interleukin-6 receptors by prostate carcinoma cell lines. , 1998, Anticancer Research.

[29]  H. Klocker,et al.  Distant metastases from prostatic carcinoma express androgen receptor protein. , 1995, Cancer research.

[30]  S. Akira,et al.  Inducible expression of nuclear factor IL-6 increases endogenous gene expression of macrophage inflammatory protein-1 alpha, osteopontin and CD14 in a monocytic leukemia cell line. , 1998, International immunology.

[31]  L. D. Ward,et al.  High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. , 1994, The Journal of biological chemistry.

[32]  A. Dunn,et al.  Functional and biochemical association of Hck with the LIF/IL‐6 receptor signal transducing subunit gp130 in embryonic stem cells. , 1994, The EMBO journal.

[33]  S. Chen‐Kiang,et al.  Regulation of terminal differentiation of human B-cells by IL-6. , 1995, Current topics in microbiology and immunology.

[34]  H. Kung,et al.  Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Richie,et al.  Future prospects in prostate cancer , 1999, The Prostate.

[36]  T. Hirano,et al.  Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK , 1997, Oncogene.

[37]  M. Kuo,et al.  Interleukin-6 Inhibits Transforming Growth Factor-β-induced Apoptosis through the Phosphatidylinositol 3-Kinase/Akt and Signal Transducers and Activators of Transcription 3 Pathways* , 1999, The Journal of Biological Chemistry.

[38]  R. Oyasu,et al.  Autocrine effect of androgen on proliferation of an androgen responsive prostatic carcinoma cell line, LNCAP: role of interleukin-6. , 1997, Endocrinology.

[39]  G. Yancopoulos,et al.  Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. , 1994, Science.

[40]  J. Ghrayeb,et al.  Synthesis and secretion of multiple forms of beta 2-interferon/B-cell differentiation factor 2/hepatocyte-stimulating factor by human fibroblasts and monocytes. , 1988, The Journal of biological chemistry.

[41]  S. Akira,et al.  Cytokine signal transduction , 1994, Cell.

[42]  P. Heinrich,et al.  The signalling pathways of interleukin-6 and gamma interferon converge by the activation of different transcription factors which bind to common responsive DNA elements , 1994, Molecular and cellular biology.

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

[44]  I. Pastan,et al.  Interleukin 6 receptor mRNA in prostate carcinomas and benign prostate hyperplasia. , 1994, The Journal of urology.

[45]  T. Kishimoto,et al.  Gp130 and the interleukin-6 family of cytokines. , 1997, Annual review of immunology.

[46]  E. Vellenga,et al.  Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components. , 2000, The Biochemical journal.

[47]  H. Klocker,et al.  Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor and epidermal growth factor. , 1995, European urology.

[48]  R. Oyasu,et al.  Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. , 1997, Cancer research.

[49]  C. Guillemette,et al.  Effect of Interleukins on UGT2B15 and UGT2B17 Steroid Uridine Diphosphate-Glucuronosyltransferase Expression and Activity in the LNCaP Cell Line. , 1998, Endocrinology.

[50]  J. Simons,et al.  Characterization of the role of IL‐6 in the progression of prostate cancer , 1999, The Prostate.

[51]  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.

[52]  A. Belldegrun,et al.  Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. , 1995, Cancer research.

[53]  S. Chevalier,et al.  gp130 Transducing Receptor Cross-linking Is Sufficient to Induce Interleukin-6 Type Responses (*) , 1996, The Journal of Biological Chemistry.

[54]  V. Devita,et al.  Cancer : Principles and Practice of Oncology , 1982 .

[55]  I. Pastan,et al.  Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. , 1990, Cancer research.

[56]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

[57]  S. Akira,et al.  Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway , 1994, Cell.

[58]  G. Stark,et al.  A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin‐6. , 1995, The EMBO journal.

[59]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[60]  H. Klocker,et al.  Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. , 1998, Cancer research.

[61]  T. Hirano,et al.  Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 , 1989, Cell.

[62]  W. Farrar,et al.  Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. , 2000, Cancer research.

[63]  P. Sehgal,et al.  Interleukin‐6‐Type Cytokines a , 1995, Annals of the New York Academy of Sciences.

[64]  T. H. van der Kwast,et al.  Androgen receptors in endocrine‐therapy‐resistant human prostate cancer , 1991, International journal of cancer.

[65]  H. Baumann,et al.  STAT3 and STAT5B Are Targets of Two Different Signal Pathways Activated by Hematopoietin Receptors and Control Transcription via Separate Cytokine Response Elements (*) , 1995, The Journal of Biological Chemistry.

[66]  H. Kung,et al.  Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells , 1998, Nature.

[67]  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.

[68]  H. Klocker,et al.  Synergistic activation of androgen receptor by androgen and luteinizing hormone‐releasing hormone in prostatic carcinoma cells , 1997, The Prostate.

[69]  D. Tweardy,et al.  Interleukin‐6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway , 2000, The Prostate.

[70]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[71]  Taylor Murray,et al.  Cancer statistics, 1999 , 1999, CA: a cancer journal for clinicians.

[72]  L. Nazareth,et al.  Activation of the Human Androgen Receptor through a Protein Kinase A Signaling Pathway* , 1996, The Journal of Biological Chemistry.

[73]  P. Heinrich,et al.  The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. , 1994, Journal of immunology.

[74]  Chawnshang Chang,et al.  Inhibition of NFκB Activity through Maintenance of IκBα Levels Contributes to Dihydrotestosterone-mediated Repression of the Interleukin-6 Promoter* , 1996, The Journal of Biological Chemistry.

[75]  K. Yasukawa,et al.  IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. , 1993, Science.

[76]  T. Hirano,et al.  Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. , 1996, The EMBO journal.

[77]  Toshio Heike,et al.  Cytoplasmic domains of the leukemia inhibitory factor receptor required for STAT3 activation, differentiation, and growth arrest of myeloid leukemic cells. , 1999, Blood.

[78]  T. Chung,et al.  Interleukin‐6 activates phosphatidylinositol‐3 kinase, which inhibits apoptosis in human prostate cancer cell lines , 2000 .

[79]  Koyanagi,et al.  High‐level production of alternatively spliced soluble interleukin‐6 receptor in serum of patients with adult T‐cell leukaemia/HTLV‐I‐associated myelopathy , 1998, Immunology.

[80]  G. Yancopoulos,et al.  Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. , 1994, The Journal of biological chemistry.

[81]  A. Dunn,et al.  gp130-mediated Signal Transduction in Embryonic Stem Cells Involves Activation of Jak and Ras/Mitogen-activated Protein Kinase Pathways* , 1996, The Journal of Biological Chemistry.

[82]  G. Strassmann,et al.  Evidence for the involvement of interleukin 6 in experimental cancer cachexia. , 1992, The Journal of clinical investigation.

[83]  J. M. Lin,et al.  Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. , 2000, The Prostate.

[84]  A. deMoura,et al.  [Cancer of the prostate]. , 1962, Jornal do medico.

[85]  H. Klocker,et al.  Immunohistochemical localization of interleukin‐6 and its receptor in benign, premalignant and malignant prostate tissue , 2000, The Journal of pathology.