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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD002285-08
Application #
8708543
Study Section
Special Emphasis Panel (ZMD1-RN)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$167,907
Indirect Cost
$50,094
Name
Clark Atlanta University
Department
Type
DUNS #
065325177
City
Atlanta
State
GA
Country
United States
Zip Code
30314
Elliott, Bethtrice; Zackery, DeAdra L; Eaton, Vanessa A et al. (2018) Ethnic differences in TGF?-signaling pathway may contribute to prostate cancer health disparity. Carcinogenesis 39:546-555
Kimbrough-Allah, Mawiyah N; Millena, Ana C; Khan, Shafiq A (2018) Differential role of PTEN in transforming growth factor ? (TGF-?) effects on proliferation and migration in prostate cancer cells. Prostate 78:377-389
Scarlett, Kisha A; White, El-Shaddai Z; Coke, Christopher J et al. (2018) Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits G?13/RhoA-mediated Migration. Mol Cancer Res 16:728-739
Caggia, Silvia; Chunduri, HimaBindu; Millena, Ana C et al. (2018) Novel role of Gi?2 in cell migration: Downstream of PI3-kinase-AKT and Rac1 in prostate cancer cells. J Cell Physiol 234:802-815
Hawsawi, Ohuod; Henderson, Veronica; Burton, Liza J et al. (2018) High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer. Biochem Biophys Res Commun 504:196-202
Burton, Liza J; Henderson, Veronica; Liburd, Latiffa et al. (2017) Snail transcription factor NLS and importin ?1 regulate the subcellular localization of Cathepsin L and Cux1. Biochem Biophys Res Commun 491:59-64
Morton, Derrick J; Patel, Divya; Joshi, Jugal et al. (2017) ID4 regulates transcriptional activity of wild type and mutant p53 via K373 acetylation. Oncotarget 8:2536-2549
Barrett, Cachétne S X; Millena, Ana C; Khan, Shafiq A (2017) TGF-? Effects on Prostate Cancer Cell Migration and Invasion Require FosB. Prostate 77:72-81
Joshi, Jugal Bharat; Patel, Divya; Morton, Derrick J et al. (2017) Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52. Mol Oncol 11:337-357
Yu, Min; Wang, Ulrica; Wang, Zhengxin (2016) E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells. Biochem J 473:2331-43

Showing the most recent 10 out of 56 publications