Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. Despite these known androgenic roles, it is unclear which specific cellular processes govern these biologys and exactly how these processes impact cellular energy demands. Preliminary results generated from the applicant's existing K01 award demonstrate that androgens regulate autophagy in prostate epithelial cells. Further, this regulation impacts overall cell metabolism, a finding that is of significance for understanding both prostatic homeostasis and disease. The long-term goal of the candidate is to develop new therapeutic approaches for the treatment of endocrine-regulated diseases such as benign prostatic hyperplasia (BPH). The primary goal of this proposal is to use a combination of metabolomics and molecular and cellular biology to define the specific role(s) of androgen-mediated autophagy in prostate epithelial cells. It is the central hypothesis that androgens, through the regulation of autophagy and subsequent fatty acid oxidation, promote cellular growth and survival. This hypothesis has been formulated on the basis of the generated preliminary data and supporting data published by other groups. The studies described in this application are designed to (a) rapidly progress our understanding of androgen receptor (AR) cellular biology and (b) generate the data necessary to build the foundation for the candidate's newly established independent research program. To accomplish these goals and test the hypothesis, two specific aims are proposed.
In Aim 1 the role of autophagy will be determined in androgen-regulated cellular processes. Preliminary studies suggest that androgens promote autophagic flux in prostate epithelial cells, a process that may result in the cellular utilization of previously unrecognized fuel sources. In this aim a fusion of molecular and cellular biology approaches will be used to both further delineate AR's regulation of autophagy and understand how androgen-mediated autophagy affects cellular growth and survival.
In Aim 2, the metabolic consequences of AR-regulated autophagy will be elucidated in prostate epithelial cells. It is hypothesized that androgen-mediated autophagy impacts cellular processes by providing cells an additional energy source(s). Initial studies indicate that autophagy leads to the breakdown of intracellular fat reservoirs, a process that could produce substrates for ?-oxidation. In this second aim, in vitro cell-based assays will be used in conjunction with emerging metabolomic technologies to mechanistically understand how AR-regulated cellular autophagy influences growth and survival. These studies will define the metabolic profile of prostate cells treated with androgens in the presence or absence of functional autophagy. Completion of these proposed aims will help the applicant define a niche that will facilitate the development of a fundable independent research program that addresses an important, but underexplored aspect of AR biology.
The proposed project is relevant to public health because it is anticipated that mechanisms identified in this study will likely yield new preventative and therapeutic approaches for prostatic diseases such as benign prostatic hyperplasia and cancer. Previous studies have demonstrated roles for increased fat metabolism and autophagy in prostatic neoplasias and as such, these processes may represent novel therapeutic targets. In addition, this new information will fundamentally advance the fields of steroid signaling and prostate biology.
|Blessing, Alicia M; Rajapakshe, Kimal; Reddy Bollu, Lakshmi et al. (2017) Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. Autophagy 13:506-521|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Gaur, Sanchaika; Wen, Yunfei; Song, Jian H et al. (2015) Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy. Oncotarget 6:29161-77|
|Shi, Yan; Han, Jenny J; Tennakoon, Jayantha B et al. (2013) Androgens promote prostate cancer cell growth through induction of autophagy. Mol Endocrinol 27:280-95|