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

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 #
2P20MD002285-06
Application #
8544044
Study Section
Special Emphasis Panel (ZMD1-RN (04))
Project Start
2012-09-05
Project End
2017-05-31
Budget Start
2012-09-05
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$169,316
Indirect Cost
$50,209
Name
Clark Atlanta University
Department
Type
DUNS #
065325177
City
Atlanta
State
GA
Country
United States
Zip Code
30314
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
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
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
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
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-? (TGF-?)-induced Inhibition of Cell Proliferation. J Biol Chem 291:17964-76
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
Han, Guang; Bi, Jianping; Tan, Wenyong et al. (2016) A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? Oncotarget 7:56998-57010
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 478:60-66
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

Showing the most recent 10 out of 51 publications