Prostate cancer is a heterogeneous disease wherein some patients demonstrate only indolent cancer which autopsy studies confirm will never metastasize from the prostate during a man's lifetime. However, worldwide over 300,000 men will die annually from metastatic disease. Distinguishing men with indolent versus aggressive prostate cancer is a major goal with global implications for morbidity and mortality. Prostate cancers demonstrate a unique altered cellular metabolism as a hallmark that corresponds with aggressiveness of dis- ease. Recent work has shown that pyruvate uptake and metabolism are significantly increased in prostate cancer relative to normal prostate tissue and associated with aggressiveness of disease. Recent work in our lab has demonstrated a subunit of the mitochondrial pyruvate carrier (MPC), MPC2, is a direct AR target gene, suggesting a link between AR action and mitochondrial heterogeneity of pyruvate trafficking. Our long-term goal is the identification, characterization, and targeted disruption of critical mediators of prostate cancer metabolism. The overall objective of the current application, is to define the mechanisms by which AR drives heterogeneous mitochondrial pyruvate trafficking to fuel lipogenesis in prostate cancer. Our central hypothesis is that AR regulates the heterogeneity of mitochondrial pyruvate flux and in turn determines the indolent versus aggressive nature of an individual's disease. The rationale of our application is that characterization of the mechanism underlying heterogeneity of pyruvate trafficking in prostate cancer will likely enable the identification of mn who need aggressive therapy versus those who do not and contribute to the development of strategies to therapeutically manipulate pyruvate flux. In order to accomplish our overall objective for the current application, we plan to test our central hypothesis by pursuing the following three specific aims: 1) Determine the impact of altered MPC subunit expression on pyruvate flux by experimentally modifying MPC subunit composition and measuring a variety of metabolic endpoints in addition to using mass-spectroscopy-based methods to perform 13C pyruvate tracing. 2) Define MPC-dependent tumor properties using in-vitro measurements of tumor cell proliferation, invasive capacity, and lipogenic capacity. 3) Assess the impact of MPC perturbation on prostate tumor growth in-vivo by transplanting nude mice with prostate cancer cells harboring stable modifications to MPC subunit expression or treating xenografted mice with the MPC inhibitor UK5099. Regarding outcomes, completion of the research plan will define the metabolic and oncogenic consequences of heterogeneous MPC subunit expression patterns observed in prostate cancer. The significance of this contribution derives from the expected translational opportunities made possible by the characterization of mechanisms underlying heterogeneous onco-metabolism, which we believe is innovative because we seek to identify and characterize mechanisms of tumor-specific metabolic heterogeneity that will translate in the future into personalized precision therapy.
The proposed research is relevant to public health and the goals of the NIH and the NCI as it seeks to improve our understanding of the metabolic changes that enable cancer cells to survive and grow, ultimately contributing to significant morbidity and mortality. It is our expectation that defining the role of heterogeneity in mitochondrial pyruvate carrier flux in determining prostate cancer progression and resistance to therapy will be an important vertical step in guiding the development of new diagnostics and therapeutic treatments to address the NCI's mission to support research to improve cancer treatment and rehabilitation.
| Koh, Eun-Hee; Chernis, Natasha; Saha, Pradip K et al. (2018) miR-30a Remodels Subcutaneous Adipose Tissue Inflammation to Improve Insulin Sensitivity in Obesity. Diabetes 67:2541-2553 |
| Jin, Feng; Thaiparambil, Jose; Donepudi, Sri Ramya et al. (2017) Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer. Cancer Prev Res (Phila) 10:588-597 |
| Kaushik, Akash K; Shojaie, Ali; Panzitt, Katrin et al. (2016) Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer. Nat Commun 7:11612 |
| Koh, Eun Hee; Chen, Yong; Bader, David A et al. (2016) Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis. J Biol Chem 291:24747-24755 |
