Prostate cancer (PCA) exhibits the most striking racial disparity as African American men are at higher risk of being diagnosed and dying of PCA, in comparison with Caucasian men. Although, multiple factors including socio-economic status contribute to this disparity but it is essential to identify the molecular and underlying biological differences that contribute to the more aggressive phenotype in African American PCA. There have been several studies investigating the genetic and epigenetic differences between African American and Caucasian PCA; however in the past, limited attention has been given to the role of tumor microenvironment contributing towards disease aggressiveness in African American PCA. In this regard, our preliminary studies discovered a unique capability of African American PCA cells to survive under hypoxic (low oxygen condition) conditions dependent upon cellular RAB5A expression, the master regulator of exosomes biogenesis, as the survival of African American PCA cells was completely compromised in RAB5A knock-down condition. More importantly, compared to Caucasian PCA cells, African American PCA cells secreted significantly higher amount of exosomes under hypoxic conditions. Interestingly, African American PCA cells seem to better adapt to hypoxia through exporting metabolic product lactic acid packaged in exosomes. Recent studies have also provided ample evidence that lactic acid is used not only as a fuel for bioenergy and biosynthesis but lactic acid also activates several mitogenic signaling pathways in various tumor microenvironment cellular components including endothelial cells, fibroblasts, macrophages and PCA cells in the normoxic areas. Taken together, we hypothesize that African American PCA cells have the unique capability to survive hypoxia via RAB5A-mediated exosomes secretion loaded with lactic acid, and the secreted exosomes promote extensive tumor microenvironment remodeling and disease aggressiveness'. Following specific aims are proposed to test our hypothesis: (I) to characterize and establish RAB5A role in exosomes secretion and survival of African American PCA cells under hypoxia; and (II) to examine and establish the role of exosomes secreted by African American PCA cells in tumor microenvironment remodeling. Proposed studies will bring a paradigm shift in our approach to understand and treat PCA in African American men brining greater focus on tumor microenvironment both for prognosis as well as treatment purposes. Overall, present proposal is highly significant and will help to narrow the huge health disparity gap faced by African American PCA patients, and reduce the PCA-caused mortality and morbidity in these patients.
Prostate cancer (PCA) exhibits the most striking racial disparity as African American men are at higher risk of being diagnosed and dying of PCA, in comparison with Caucasian men, and therefore this is an important public health issue. Proposed studies will bring a paradigm shift in our approach to understand and treat PCA in African American men brining greater focus on tumor microenvironment both for prognosis as well as treatment purposes. This will help to narrow the huge health disparity gap faced by African American PCA patients, and reduce the PCA-caused mortality and morbidity in these patients.
|Deep, Gagan; Kumar, Rahul; Nambiar, Dhanya K et al. (2017) Silibinin inhibits hypoxia-induced HIF-1?-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics. Mol Carcinog 56:833-848|
|Panigrahi, Gati Krushna; Deep, Gagan (2017) Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer. Front Biosci (Landmark Ed) 22:1682-1696|
|Deep, Gagan; Schlaepfer, Isabel R (2016) Aberrant Lipid Metabolism Promotes Prostate Cancer: Role in Cell Survival under Hypoxia and Extracellular Vesicles Biogenesis. Int J Mol Sci 17:|
|Deep, Gagan; Kumar, Rahul; Jain, Anil K et al. (2016) Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci Rep 6:23135|
|Deep, Gagan; Panigrahi, Gati K (2015) Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment. Crit Rev Oncog 20:419-34|