The Jun Kinase/Stress-activated protein kinase pathway (JNK/SAPK) has been implicated as mediating stress-responses, survival, proliferation, and apoptosis. Previous studies, principally by C. Der and co-workers and M. Karin, in which this laboratory participated, have shown the JNK pathway is required for the transformation of primary fibroblasts by the activated ras oncogene and related oncogenes. We have extended the JNK analysis to human tumor cells. JNK is commonly serum-inducible or constitutively active in a variety of human tumor cells. Specific inhibition blocks tumor cell growth. Moreover, stable expression of a dominant negative inhibitor, c-Jun (S63A, S73A), blocks DNA repair and greatly sensitizes human tumor lines (T98G glioblastoma, A549 lung, MCF-7 breast, and PC3 prostate carcinoma) to killing by cisplatin, up to 9.7-fold for PC3 cells. We hypothesize that during progression of cancer, the JNK pathway is commonly selected as greatly enhancing DNA repair and synthesis, thereby facilitating oncongenesis. To test this, highly specific antisense compounds complementary to the two isoform families JNK1 and JNK2 have been developed and characterized. Systemic antisense treatment of athymic mice bearing established PC3 xenografts inhibits growth by 79 percent, better than cisplatin (49 percent), and combined antisense treatment promotes complete regression in high frequency. Conversely, PC3 cells are 100 percent tumorigenic. To test the generality, eight additional prostate cell lines were found to proliferate in direct proportion to the serum-inducible level of JNK activity over a 9-fold range. Moreover antisense JNK2 but not antisense JNK1 nearly completely blocks the growth of all lines in proportion to the JNK activity strongly indicating that JNK2 is commonly required for serum-stimulated growth prostate carcinoma cells. It is proposed to test the hypothesis that JNK is oncogenic in prostate carcinoma. We will test whether JNK is required for proliferation of prostate carcinoma lines in vitro (Aim 1) and in vivo (Aim 2). The efficacy of antisense JNK will be tested critically in the TRAMP model (Aim 2). The mechanism of oncogenesis by JNK will be tested by determining whether predicted DNA synthesis genes are expressed in tumor cells (Aim 3) and prostate tumor specimens (Aim 4) using established cDNA arrays. Microarrays will be constructed that utilize 35,000 NIH/CGAP sequence verified cancer expression library obtained by cloning from laser capture microdissection human tumor specimens. These studies test a novel hypothesis and test the utility of new inhibitors for the treatment of prostate carcinoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Perry, Mary Ellen
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Sidney Kimmel Cancer Center
San Diego
United States
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