This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, Y.-M. Articles by Mercola, D. Search for Related Content PubMed PubMed Citation Articles by Yang, Y.-M. Articles by Mercola, D.

C-Jun NH₂-terminal Kinase Mediates Proliferation and Tumor Growth of Human Prostate Carcinoma¹

Sidney Kimmel Cancer Center, San Diego, California 92121 [Y-M. Y., F. B., W. C., C. D., D. M.]; Isis Pharmaceutical Inc., Carlsbad, California 92008 [N. D., R. M.]; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 [J. S. R.]; and Cancer Center, University of California at San Diego, San Diego, California, 92093 [D. M.]

Purpose: C-Jun NH₂-terminal kinase (JNK) has been implicated in numerous functions including stress responses, apoptosis,and transformation. The role in transformation is based largely on studies of isolated cell types with little indication of whether JNK plays a general role in a specific human tumor type or whether this occurs in vivo.

Experimental Design: We examined 9 human prostate carcinoma cell lines in vitro and a representative line in vivo.

Results: For all of the cell lines proliferation is highly correlated with serum-supported JNK activity (r_Pearson = 0.91; P = 0.004), whereas no relationship was observed for 10 human breast cancer cell lines (r_Pearson = -0.32). Treatment with characterized antisense oligonucleotides complementary to sequences common to either the JNK1 or JNK2 family of isoforms showed that, whereas antisense JNK1 inhibited growth by a maximum of 57%, antisense JNK2 inhibited proliferation up to 80%. Sense and scrambled control oligonucleotides had little effect (average 3.7 ± 1.5%). Moreover, systemic treatment of mice bearing established xenografts of PC3 prostate carcinoma cells with antisense JNK1 and JNK2 led to inhibition tumor growth by 57% (P < 0.002) and 80% (P < 0.001), respectively. The difference is significant (P < 0.012). Combined antisense treatment led to a significant increase in frequency of tumor regression (P = 0.022).

Conclusion: These results indicate that JNK is required for growth of prostate carcinoma cells in vitro and in vivo, and additionally indicate that JNK2 plays a dominant role. The JNK pathway is a novel target in the treatment of prostate carcinoma.

This article has been cited by other articles:

				J.-S. Diallo, A. Aldejmah, A. F. Mouhim, B. Peant, M. A. Fahmy, I. H. Koumakpayi, K. Sircar, L. R. Begin, A.-M. Mes-Masson, and F. Saad NOXA and PUMA Expression Add to Clinical Markers in Predicting Biochemical Recurrence of Prostate Cancer Patients in a Survival Tree Model Clin. Cancer Res., December 1, 2007; 13(23): 7044 - 7052. [Abstract] [Full Text] [PDF]

				N. D. Gross, J. O. Boyle, B. Du, V. D. Kekatpure, A. Lantowski, H. T. Thaler, B. B. Weksler, K. Subbaramaiah, and A. J. Dannenberg Inhibition of Jun NH2-Terminal Kinases Suppresses the Growth of Experimental Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., October 1, 2007; 13(19): 5910 - 5917. [Abstract] [Full Text] [PDF]

				J. Y. Zhang, A. E. Adams, T. W. Ridky, S. Tao, and P. A. Khavari Tumor Necrosis Factor Receptor 1/c-Jun-NH2-Kinase Signaling Promotes Human Neoplasia Cancer Res., April 15, 2007; 67(8): 3827 - 3834. [Abstract] [Full Text] [PDF]

				A. G. Papatsoris, M. V. Karamouzis, and A. G. Papavassiliou The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics Mol. Cancer Ther., March 1, 2007; 6(3): 811 - 819. [Abstract] [Full Text] [PDF]

				C. Nielsen, J. Thastrup, T. Bottzauw, M. Jaattela, and T. Kallunki c-Jun NH2-Terminal Kinase 2 Is Required for Ras Transformation Independently of Activator Protein 1 Cancer Res., January 1, 2007; 67(1): 178 - 185. [Abstract] [Full Text] [PDF]

				N. Lopez-Sanchez, J.-R. Rodriguez, and J. M. Frade Mitochondrial c-Jun NH2-Terminal Kinase Prevents the Accumulation of Reactive Oxygen Species and Reduces Necrotic Damage in Neural Tumor Cells that Lack Trophic Support Mol. Cancer Res., January 1, 2007; 5(1): 47 - 60. [Abstract] [Full Text] [PDF]

				J. Cui, S.-Y. Han, C. Wang, W. Su, L. Harshyne, M. Holgado-Madruga, and A. J. Wong c-Jun NH2-Terminal Kinase 2{alpha}2 Promotes the Tumorigenicity of Human Glioblastoma Cells. Cancer Res., October 15, 2006; 66(20): 10024 - 10031. [Abstract] [Full Text] [PDF]

				D. W. Lin, I. M. Coleman, S. Hawley, C. Y. Huang, R. Dumpit, D. Gifford, P. Kezele, H. Hung, B. S. Knudsen, A. R. Kristal, et al. Influence of Surgical Manipulation on Prostate Gene Expression: Implications for Molecular Correlates of Treatment Effects and Disease Prognosis J. Clin. Oncol., August 10, 2006; 24(23): 3763 - 3770. [Abstract] [Full Text] [PDF]

				B. W. Ennis, K. E. Fultz, K. A. Smith, J. K. Westwick, D. Zhu, M. Boluro-Ajayi, G. K. Bilter, and B. Stein Inhibition of Tumor Growth, Angiogenesis, and Tumor Cell Proliferation by a Small Molecule Inhibitor of c-Jun N-terminal Kinase J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 325 - 332. [Abstract] [Full Text] [PDF]

				J. Cui, M. Holgado-Madruga, W. Su, H. Tsuiki, P. Wedegaertner, and A. J. Wong Identification of a Specific Domain Responsible for JNK2{alpha}2 Autophosphorylation J. Biol. Chem., March 18, 2005; 280(11): 9913 - 9920. [Abstract] [Full Text] [PDF]

				W. Reiley, M. Zhang, and S.-C. Sun Negative Regulation of JNK Signaling by the Tumor Suppressor CYLD J. Biol. Chem., December 31, 2004; 279(53): 55161 - 55167. [Abstract] [Full Text] [PDF]

				R. A. MacCorkle and T.-H. Tan Inhibition of JNK2 Disrupts Anaphase and Produces Aneuploidy in Mammalian Cells J. Biol. Chem., September 17, 2004; 279(38): 40112 - 40121. [Abstract] [Full Text] [PDF]

				J. F. Curtin and T. G. Cotter JNK Regulates HIPK3 Expression and Promotes Resistance to Fas-mediated Apoptosis in DU 145 Prostate Carcinoma Cells J. Biol. Chem., April 23, 2004; 279(17): 17090 - 17100. [Abstract] [Full Text] [PDF]

				L. Gate, R. S. Majumdar, A. Lunk, and K. D. Tew Increased Myeloproliferation in Glutathione S-Transferase {pi}-deficient Mice Is Associated with a Deregulation of JNK and Janus Kinase/STAT Pathways J. Biol. Chem., March 5, 2004; 279(10): 8608 - 8616. [Abstract] [Full Text] [PDF]

				V. BARON, S. DUSS, J. RHIM, and D. MERCOLA Antisense to the Early Growth Response-1 Gene (Egr-1) Inhibits Prostate Tumor Development in TRAMP Mice Ann. N.Y. Acad. Sci., December 1, 2003; 1002(1): 197 - 216. [Abstract] [Full Text] [PDF]

				C. Vivo, W. Liu, and V. C. Broaddus c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells J. Biol. Chem., July 3, 2003; 278(28): 25461 - 25467. [Abstract] [Full Text] [PDF]