African-American men are disproportionately affected by prostate cancer. African-American men have 65% higher incidence rate and more than twice the mortality rate due to prostate cancer when compared with Caucasian men. Prostate cancer is also diagnosed at a more advanced stage at an earlier age in African- American men. Previous studies in breast and endometrial cancer suggested an important role of TGF Beta3 (vs TGF Beta1) in metastatic disease. Recent studies have shown that peripheral blood TGF-Beta1 protein levels are associated with body mass index, microalbumuria, plasma renin activity, and metabolic syndrome in African Americans but not in Caucasians. Overexpression of TGF-Beta1 was significantly higher in African- Americans patients than in Caucasian patients with hypertension, diabetes, glaucoma and end stage renal disease. In our recent studies, we determined the expression of three TGF-B isoforms (-B1, B2 and B3) in several prostate cell lines representing normal epithelial cells and various stages of cancer progression. These studies revealed that TGF-Beta1 mRNA and protein were expressed by all cell lines. On the other hand, TGF- Beta3 mRNA and protein are expressed at very low levels in normal prostate epithelial cells but are expressed at very high levels in prostate cancer cell lines representing metastatic stages of the disease. Our continued studies revealed that TGF- Beta3 exerts significant effects on migration and invasive behavior of prostate cancer cells and that this isoform is significantly more potent than TGF- Beta3 in exerting these effects. We also found that these effects of TGF- Beta3 on migration and invasion are mediated by the Beta3-kinase/AKT signaling pathway. The studies proposed in this grant will test the hypothesis that the increased expression of TGF- Beta3 in later stages of cancer may be involved in rapid progression of the metastatic disease. Additionally, higher levels of this cytokine in African-American men may be responsible for increased incidence and mortality due to prostate cancer. These studies will focus on 1) determination of the expression of TGF- Beta isoforms, 2) the activation of PI3-kinase signaling pathway by TGF- Beta3 and, 3) the mechanisms by which TGF-Beta may regulate the invasive behavior of prostate cancer cells.

Public Health Relevance

These studies are relevant to the understanding of the cellular and molecular mechanisms involved in the migration and invasive behavior of prostate cancer cells and the resulting metastatic disease. The studies will also try to understand mechanisms involved in prostate cancer health disparities in African-American men.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
4P20MD002285-10
Application #
9066520
Study Section
Special Emphasis Panel (ZMD1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Clark Atlanta University
Department
Type
DUNS #
065325177
City
Atlanta
State
GA
Country
United States
Zip Code
30314
Barrett, Cach├ętne 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