The inflammation-to-carcinoma sequence is common in the development of prostate cancer (PCa). Inherited mutations in acute inflammatory genes such as tumor suppressor RNaseL influence the susceptibility of prostate cells to infection and are associated with increased risk for PCa. However, these mutations are rare, low penetrant and account for less than 2% of all PCa. In contrast, common genetic variations, such as low penetrant single nucleotide polymorphisms (SNP) in a large group of genes, are more likely to contribute to majority of sporadic prostate cancer cases. 2'-5'Oligoadenylate synthetase 1 (OASI), an androgen and IFN regulated gene within the inflammatory pathway converts ATP to 2'-5'-oligoadenylates (2-5A) which in turn activates RNaseL. Thus OASI is a rate limiting enzyme involved in generating RNaseL dependent anti-tumor response. Our studies have demonstrated that OASI is inversely correlated with increasing grade of PCa and that a functional nonsynonymous genetic variation in OASI is associated with PCa risk. However, significant questions regarding the effect of OASI genetic variations on survival and its mechanism of action in prostate cancer remains to be investigated. In order to address these questions we propose our hypothesis that """"""""OASI expression or enzyme activity required to generate an anti-tumor response independently or as part of the RNaseL pathway is absent or attenuated in prostate cancer due to single nucleotide polymorphism and leads to increased morbidity and mortality specifically in African American population"""""""".
Two specific aims are proposed: 1. Investigate the association between OASI germ line variations with prostate cancer and racial disparity and 2. Investigate the biological significance of OAS1 in prostate cancer. Association studies from our laboratory have shown that a specific OASI genotype (rs2660: GG) that protects against prostate cancer is not present in a large cohort of African American population. These results are particularly interesting since racial disparities exist between prostate cancer incidence/ survival indicating intrinsic differences in genetics and tumor biology.
OASI, alone or in association with RNaseL could be a prostate cancer susceptibility gene in general and African American population in perticular. Lack of OASI is expected to increase susceptibility to infections, suppress anti-tumor acute inflammatory response and promote prostate cancer. Loss of 0AS1 will also provide mechanistic basis for sporadic prostate cancer cases in which no RNaseL mutations are observed.
|Sheng, Xiumei; Wang, Zhengxin (2016) Protein arginine methyltransferase 5 regulates multiple signaling pathways to promote lung cancer cell proliferation. BMC Cancer 16:567|
|Sheng, Xiumei; Bowen, Nathan; Wang, Zhengxin (2016) GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer. Mol Cancer 15:25|
|Bhosle, Sushma M; Hunt, Aisha; Chaudhary, Jaideep (2016) A Modified Coupled Spectrophotometric Method to Detect 2-5 Oligoadenylate Synthetase Activity in Prostate Cell Lines. Biol Proced Online 18:9|
|Komaragiri, Shravan Kumar; Bostanthirige, Dhanushka H; Morton, Derrick J et al. (2016) ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells. Biochem Biophys Res Commun 478:60-6|
|Millena, Ana Cecilia; Vo, BaoHan T; Khan, Shafiq A (2016) JunD Is Required for Proliferation of Prostate Cancer Cells and Plays a Role in Transforming Growth Factor-Î² (TGF-Î²)-induced Inhibition of Cell Proliferation. J Biol Chem 291:17964-76|
|Patel, Divya; Morton, Derrick J; Carey, Jason et al. (2015) Inhibitor of differentiation 4 (ID4): From development to cancer. Biochim Biophys Acta 1855:92-103|
|Chinaranagari, Swathi; Sharma, Pankaj; Bowen, Nathan J et al. (2015) Prostate cancer epigenome. Methods Mol Biol 1238:125-40|
|Henderson, Veronica; Smith, Basil; Burton, Liza J et al. (2015) Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adh Migr 9:255-64|
|Brown, Shanora G; Knowell, Ashley E; Hunt, Aisha et al. (2015) Interferon inducible antiviral MxA is inversely associated with prostate cancer and regulates cell cycle, invasion and Docetaxel induced apoptosis. Prostate 75:266-79|
|Burton, Liza J; Smith, Basil A; Smith, Bethany N et al. (2015) Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells. Carcinogenesis 36:1019-27|
Showing the most recent 10 out of 45 publications