NF‐κB activation in human prostate cancer: Important mediator or epiphenomenon?

The NF‐κB family of transcription factors has been shown to be constitutively activated in various human malignancies, including leukemias, lymphomas, and a number of solid tumors. NF‐κB is hypothesized to contribute to development and/or progression of malignancy by regulating the expression of genes involved in cell growth and proliferation, anti‐apoptosis, angiogenesis, and metastasis. Prostate cancer cells have been reported to have constitutive NF‐κB activity due to increased activity of the IκB kinase complex. Furthermore, an inverse correlation between androgen receptor (AR) status and NF‐κB activity was observed in prostate cancer cell lines. NF‐κB may promote cell growth and proliferation in prostate cancer cells by regulating expression of genes such as c‐myc, cyclin D1, and IL‐6. NF‐κB may also inhibit apoptosis in prostate cancer cells through activation of expression of anti‐apoptotic genes, such as Bcl‐2, although pro‐apoptotic activity of NF‐κB has also been reported. NF‐κB‐mediated expression of genes involved in angiogenesis (IL‐8, VEGF), and invasion and metastasis (MMP9, uPA, uPA receptor) may further contribute to the progression of prostate cancer. Constitutive NF‐κB activity has also been demonstrated in primary prostate cancer tissue samples and suggested to have prognostic importance for a subset of primary tumors. The limited number of samples analyzed in those studies and the relative lack of NF‐κB target genes identified in RNA expression microarray analyses of prostate cancer cells suggest that further studies will be required in order to determine if NF‐κB actually plays a role in human prostate cancer development, and/or progression, and to characterize its potential as a therapeutic target. © 2003 Wiley‐Liss, Inc.

[1]  T. Barrette,et al.  Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer. , 2002, Cancer research.

[2]  W. Zong,et al.  Mechanisms of constitutive NF‐κB activation in human prostate cancer cells , 2002, The Prostate.

[3]  G. Sledge,et al.  Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth , 1997, Molecular and cellular biology.

[4]  M. Bittner,et al.  Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. , 2001, Cancer research.

[5]  W. Liu,et al.  Up-regulation of Akt3 in Estrogen Receptor-deficient Breast Cancers and Androgen-independent Prostate Cancer Lines* , 1999, The Journal of Biological Chemistry.

[6]  V. Rangnekar,et al.  Apoptosis by Par-4 in cancer and neurodegenerative diseases. , 2003, Experimental cell research.

[7]  K. Shimada,et al.  Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis. , 2003, Carcinogenesis.

[8]  S. Catz,et al.  Transcriptional regulation of bcl-2 by nuclear factor κB and its significance in prostate cancer , 2001, Oncogene.

[9]  M. May,et al.  Signal transduction through NF-kappa B. , 1998, Immunology today.

[10]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[11]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[12]  A. Miyajima,et al.  An essential role for nuclear factor kappa B in preventing TNF-alpha-induced cell death in prostate cancer cells. , 1999, The Journal of urology.

[13]  Marty W. Mayo,et al.  Akt Stimulates the Transactivation Potential of the RelA/p65 Subunit of NF-κB through Utilization of the IκB Kinase and Activation of the Mitogen-activated Protein Kinase p38* , 2001, The Journal of Biological Chemistry.

[14]  E. Lander,et al.  Gene expression correlates of clinical prostate cancer behavior. , 2002, Cancer cell.

[15]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[16]  W. Isaacs,et al.  Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. , 1998, Cancer research.

[17]  H. Erdjument-Bromage,et al.  The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. , 1997, Cell.

[18]  Hong-shan Wang,et al.  BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells , 2002, Nature Immunology.

[19]  Michael Karin,et al.  Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling Pathway , 2001, Science.

[20]  B. Huhse,et al.  CD40 regulates the processing of NF‐κB2 p100 to p52 , 2002 .

[21]  C. Bucana,et al.  Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. , 2001, Oncogene.

[22]  C. Y. Wang,et al.  TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. , 1996, Science.

[23]  R. Surabhi,et al.  TAK1 is Critical for IκB Kinase-mediated Activation of the NF-κB Pathway , 2003 .

[24]  Y. Oshika,et al.  P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo. , 1996, British Journal of Cancer.

[25]  M. Ittmann,et al.  Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  T. Maniatis,et al.  Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. , 1997, Cell.

[27]  Quan Zhao,et al.  Mitogen-activated Protein Kinase/ERK Kinase Kinases 2 and 3 Activate Nuclear Factor-κB through IκB Kinase-α and IκB Kinase-β* , 1999, The Journal of Biological Chemistry.

[28]  V. Rangnekar,et al.  Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. , 2001, Cancer research.

[29]  D. Seldin,et al.  Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. , 2001, Cancer research.

[30]  H. Pahl,et al.  Phosphorylation of human I kappa B‐alpha on serines 32 and 36 controls I kappa B‐alpha proteolysis and NF‐kappa B activation in response to diverse stimuli. , 1995, The EMBO journal.

[31]  A. Baldwin,et al.  Activation of Nuclear Factor-κB-dependent Transcription by Tumor Necrosis Factor-α Is Mediated through Phosphorylation of RelA/p65 on Serine 529* , 1998, The Journal of Biological Chemistry.

[32]  R. Ratan,et al.  The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. , 2001, The Journal of biological chemistry.

[33]  H. Erdjument-Bromage,et al.  The Transcriptional Activity of NF-κB Is Regulated by the IκB-Associated PKAc Subunit through a Cyclic AMP–Independent Mechanism , 1997, Cell.

[34]  C. Bucana,et al.  Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis , 2001, Oncogene.

[35]  C. Bucana,et al.  Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. , 2000, Cancer research.

[36]  David Baltimore,et al.  NF-κB: Ten Years After , 1996, Cell.

[37]  Douglas B. Evans,et al.  The Nuclear Factor-κB RelA Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells , 1999 .

[38]  A. E. Rogers,et al.  Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. , 1997, The Journal of clinical investigation.

[39]  W. Funkhouser,et al.  Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3 , 2000, Oncogene.

[40]  L. Lessard,et al.  NF‐κB nuclear localization and its prognostic significance in prostate cancer , 2003 .

[41]  S. Dower,et al.  Activation of Nuclear Transcription Factor NF-κB by Interleukin-1 Is Accompanied by Casein Kinase II-mediated Phosphorylation of the p65 Subunit* , 1997, The Journal of Biological Chemistry.

[42]  R. Hay,et al.  Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IκBα , 1999, Oncogene.

[43]  Michael Karin,et al.  NF-κB in cancer: from innocent bystander to major culprit , 2002, Nature Reviews Cancer.

[44]  R. Agarwal,et al.  Silibinin inhibits constitutive and TNFα-induced activation of NF-κB and sensitizes human prostate carcinoma DU145 cells to TNFα-induced apoptosis , 2002, Oncogene.

[45]  W. Liao,et al.  The essential role of MEKK3 in TNF-induced NF-kappaB activation. , 2001, Nature immunology.

[46]  P. Dhawan,et al.  Correction: A Novel NF-κB-inducing Kinase-MAPK Signaling Pathway Up-regulates NF-κB Activity in Melanoma Cells , 2001, The Journal of Biological Chemistry.

[47]  C. N. Coleman,et al.  Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen , 1999, Oncogene.

[48]  E. Kikuchi,et al.  Suppression of hormone-refractory prostate cancer by a novel nuclear factor kappaB inhibitor in nude mice. , 2003, Cancer research.

[49]  A. Baldwin.  Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. , 2001, The Journal of clinical investigation.

[50]  D. Green,et al.  The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways , 2002 .

[51]  R. Agarwal,et al.  Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. , 2002, Oncogene.

[52]  R. Schmid,et al.  Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. , 2001, Cancer research.

[53]  A. Pardee,et al.  Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Van Waes,et al.  Constitutive activation of transcription factors NF‐κB, AP‐1, and NF‐IL6 in human head and neck squamous cell carcinoma cell lines that express pro‐inflammatory and pro‐angiogenic cytokines , 1999, Molecular carcinogenesis.

[55]  C. Sawyers,et al.  NF-κB Activates Prostate-Specific Antigen Expression and Is Upregulated in Androgen-Independent Prostate Cancer , 2002, Molecular and Cellular Biology.

[56]  P. Baeuerle,et al.  Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-kappaB activation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[57]  N Nonomura,et al.  Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. , 2001, Journal of the National Cancer Institute.

[58]  T. Ikonen,et al.  Mutual Transcriptional Interference between RelA and Androgen Receptor* , 1996, The Journal of Biological Chemistry.

[59]  W. McBride,et al.  Inhibition of NF-κB, Clonogenicity, and Radiosensitivity of Human Cancer Cells , 1999 .

[60]  C. Mueller-Dieckmann,et al.  Tyrosine Phosphorylation of IκB-α Activates NF-κB without Proteolytic Degradation of IκB-α , 1996, Cell.

[61]  R. Uzzo,et al.  Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  T. McDonnell,et al.  Bcl-2 suppresses apoptosis resulting from disruption of the NF-κB survival pathway , 1997 .

[63]  E. Gelmann,et al.  Propapoptotic effects of NF-κB in LNCaP prostate cancer cells lead to serine protease activation , 2002, Cell Death and Differentiation.

[64]  T. Gilmore.  Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel , 1999, Oncogene.

[65]  G. Dong,et al.  Expression of a Dominant-Negative Mutant Inhibitor-κBα of Nuclear Factor-κB in Human Head and Neck Squamous Cell Carcinoma Inhibits Survival, Proinflammatory Cytokine Expression, and Tumor Growth in Vivo , 1999 .

[66]  C. Bucana,et al.  Nuclear factor-kappaB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[67]  P. Roy-Burman,et al.  Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer. , 1995, The American journal of pathology.

[68]  F. Lee,et al.  Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. , 1999, The Journal of biological chemistry.

[69]  R. Weindruch,et al.  Effect of antioxidants on androgen-induced AP-1 and NF-kappaB DNA-binding activity in prostate carcinoma cells. , 1999, Journal of the National Cancer Institute.

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

[71]  D. Goeddel,et al.  Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. , 2001, Science.

[72]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[73]  Y. Liaw,et al.  Constitutive activation of nuclear factor κB in hepatocellular carcinoma , 2000 .

[74]  A. Neri,et al.  The involvement of the candidate proto-oncogene NFKB2/lyt-10 in lymphoid malignancies. , 1996, Leukemia & lymphoma.

[75]  C. Bucana,et al.  Nuclear Factor-κB Activity Correlates with Growth, Angiogenesis, and Metastasis of Human Melanoma Cells in Nude Mice , 2000 .

[76]  D. Green,et al.  The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. , 2002, Immunity.

[77]  Douglas B. Evans,et al.  Function of nuclear factor kappaB in pancreatic cancer metastasis. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[78]  S. Ghosh,et al.  Signal transduction through NF-κB , 1998 .

[79]  B. Aggarwal,et al.  Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines , 2001, Oncogene.

[80]  G. Sledge,et al.  Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide. , 2000, Oncogene.

[81]  C. Gélinas,et al.  Rearrangement and altered expression of the NFKB-2 gene in human cutaneous T-lymphoma cells. , 1994, Oncogene.

[82]  R. Ratan,et al.  The Epidermal Growth Factor Receptor Engages Receptor Interacting Protein and Nuclear Factor-κB (NF-κB)-inducing Kinase to Activate NF-κB , 2001, The Journal of Biological Chemistry.

[83]  S. Westerheide,et al.  Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. , 2000, The Journal of biological chemistry.

[84]  Jingqing Yang,et al.  Constitutive IκB Kinase Activity Correlates with Nuclear Factor-κB Activation in Human Melanoma Cells , 2001 .

[85]  Hong-shan Wang,et al.  BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. , 2002, Nature immunology.

[86]  J. Fitzpatrick,et al.  Androgen‐mediated resistance to apoptosis , 2002, The Prostate.

[87]  R. Surabhi,et al.  TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. , 2003, Journal of molecular biology.

[88]  L. Lessard,et al.  NF-kappa B nuclear localization and its prognostic significance in prostate cancer. , 2003, BJU international.

[89]  R. Coffey,et al.  Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. , 2001, Oncogene.

[90]  C. Van Waes,et al.  Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines , 2002, International journal of cancer.

[91]  T. Maniatis,et al.  Activation of the IκBα Kinase Complex by MEKK1, a Kinase of the JNK Pathway , 1997, Cell.

[92]  M. Karin,et al.  Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. , 2001, Science.

[93]  T. Mak,et al.  Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. , 2000, Genes & development.

[94]  T. Slaga,et al.  The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. , 2002, Journal of cell science.

[95]  D. Goeddel,et al.  TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. , 2002, Molecular cell.

[96]  Ulrich Siebenlist,et al.  Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells , 2001, The Journal of experimental medicine.

[97]  D. Wang,et al.  Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. , 1998, The Journal of biological chemistry.

[98]  C. Sawyers,et al.  NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. , 2002, Molecular and cellular biology.

[99]  A. Richmond,et al.  Enhanced Degradation of I-κBα Contributes to Endogenous Activation of NF-κB in Hs294T Melanoma Cells , 1997 .

[100]  T. Libermann,et al.  Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. , 2003, Cancer research.

[101]  Debajit K. Biswas,et al.  Epidermal growth factor-induced nuclear factor κB activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells , 2000 .

[102]  B. Rayet,et al.  Aberrant rel/nfkb genes and activity in human cancer , 1999, Oncogene.

[103]  Chao-yuan Huang,et al.  Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21WAF1/CIP1 and C/EBPβ expressions and suppressing NF‐κB activation , 2002, The Prostate.

[104]  G. Sledge,et al.  Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide , 2000, Oncogene.

[105]  Y. Liaw,et al.  Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. , 2000, Cancer.

[106]  Jeffrey A. Magee,et al.  Expression profiling reveals hepsin overexpression in prostate cancer. , 2001, Cancer research.

[107]  S. Ghosh,et al.  Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. , 1998, Molecular cell.

[108]  B. Dörken,et al.  Molecular mechanisms of constitutive NF-κB/Rel activation in Hodgkin/Reed-Sternberg cells , 1999, Oncogene.

[109]  F. Sarkar,et al.  Genistein inhibits NF-kappa B activation in prostate cancer cells. , 1999, Nutrition and cancer.

[110]  Nanxin Li,et al.  Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

[112]  C. N. Coleman,et al.  Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. , 1999, Oncogene.

[113]  W. Greene,et al.  Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF‐κB , 2002, The EMBO journal.

[114]  Matthias Kretzler,et al.  Decrease and gain of gene expression are equally discriminatory markers for prostate carcinoma: a gene expression analysis on total and microdissected prostate tissue. , 2002, The American journal of pathology.

[115]  Michael Karin,et al.  NF-kappaB at the crossroads of life and death. , 2002, Nature immunology.

[116]  W. Funkhouser,et al.  Selective activation of NF-kappa B subunits in human breast cancer: potential roles for NF-kappa B2/p52 and for Bcl-3. , 2000, Oncogene.

[117]  S. Westerheide,et al.  Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II* , 2000, The Journal of Biological Chemistry.

[118]  S. Gerstberger,et al.  Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation , 1995, Science.

[119]  E. Zandi,et al.  Bridging the Gap: Composition, Regulation, and Physiological Function of the IκB Kinase Complex , 1999, Molecular and Cellular Biology.

[120]  D. Carrasco,et al.  The v‐rel oncogene promotes malignant T‐cell leukemia/lymphoma in transgenic mice. , 1996, The EMBO journal.

[121]  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.

[122]  A. Richmond,et al.  Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. , 1997, Cancer research.

[123]  Douglas B. Evans,et al.  Function of Nuclear Factor κB in Pancreatic Cancer Metastasis , 2003 .

[124]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[125]  W. Liao,et al.  The essential role of MEKK3 in TNF-induced NF-κB activation , 2001, Nature Immunology.

[126]  B. Huhse,et al.  CD40 regulates the processing of NF-kappaB2 p100 to p52. , 2002, The EMBO journal.

[127]  Michael Karin,et al.  NF-κB at the crossroads of life and death , 2002, Nature Immunology.

[128]  Michael Karin,et al.  NF-kappaB in cancer: from innocent bystander to major culprit. , 2002, Nature reviews. Cancer.

[129]  C. Mueller-Dieckmann,et al.  Tyrosine Phosphorylation of IkB-a Activates NF-kB without Proteolytic Degradation of IkB-a , 1996 .

[130]  Mansoor M Ahmed,et al.  Par-4, A Pro-Apoptotic Gene, Inhibits Radiation-Induced NFκB Activity and Bcl-2 Expression Leading to Induction of Radiosensitivity in Human Prostate Cancer Cells PC-3 , 2002, Cancer biology & therapy.

[131]  P. Dhawan,et al.  A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. , 2002, The Journal of biological chemistry.

[132]  Michael Karin,et al.  Positive and Negative Regulation of IκB Kinase Activity Through IKKβ Subunit Phosphorylation , 1999 .

[133]  J. Welsh,et al.  Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. , 2001, Cancer research.

[134]  Mitsutoshi Nakamura,et al.  Contributions of mitogen‐activated protein kinase and nuclear factor kappa B to N‐(4‐hydroxyphenyl)retinamide–induced apoptosis in prostate cancer cells , 2002, Molecular carcinogenesis.

[135]  D. Auerbach,et al.  Tissue-specific Isoforms of Chicken Myomesin Are Generated by Alternative Splicing* , 1996, The Journal of Biological Chemistry.

[136]  D. Goeddel,et al.  Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice , 2001, Science.

[137]  P. Dhawan,et al.  Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. , 2002, Cancer research.

[138]  T. McDonnell,et al.  Bcl-2 suppresses apoptosis resulting from disruption of the NF-kappa B survival pathway. , 1997, Experimental cell research.

[139]  M. Karin,et al.  Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. , 1999, Science.

[140]  Rajiv Dhir,et al.  Gene expression analysis of prostate cancers , 2002, Molecular carcinogenesis.