Elucidating the Role of Glucose Metabolism in Prostate Cancer

Date

2015-12

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Abstract

Prostate cancer is a complex disease. Despite the progress in early detection and treatment, the progression to castration-resistant prostate cancer (CRPC) is inevitable for some patients and the survival window is only extended to approximately two-three years with current therapeutic options. Identifying new therapeutic targets for prostate cancer treatment is crucial. An important aspect of the tumor growth is metabolic rewiring. Androgens increase glucose uptake and subsequently glycolysis and PPP flux. I investigated how Androgen receptor (AR) signaling regulated the pentose phosphate pathway (PPP), a commonly overshadowed metabolic pathway. The activation of PPP happens in part via regulation of the rate-limiting enzyme of PPP, glucose-6-phosphate dehydrogenase (G6PD). G6PD was demonstrated to be regulated via an AR-mTOR signaling cascade and was important for proliferation, NADPH generation, ROS scavenging and ribose synthesis in prostate cancer cells. Further investigation led to the elucidation of the regulation of the committed step of glycolysis, phosphofructokinase-1 (PFK1). PFK1 is regulated allosterically via the metabolite fructose-2,6-bisphosphate. This metabolite is synthesized or degraded by the actions of phosphofructokinase fructose bisphosphate (PFKFB). Androgen receptor signaling, mTOR and AMPK regulate the transcription of PFKFB2 and PFKFB3. Additionally, the CAMKK2-AMPK signaling axis, which is regulated by AR, regulates the activity of PFKFB2 and PFKFB3 via phosphorylation. Pharmacological inhibition of PFKFB3 using PFK15 in CRPC AR+ and AR- prostate cancer cells demonstrated that PFK15 blocked glucose uptake, glycolysis and cell growth. These results highlight PFKFB2 and 3 potential as a therapeutic target in advanced prostate cancers. Finally, investigation of how AR signaling regulates glucose uptake to support an increase of the glycolytic and PPP flux has led to the identification of a new direct target of AR, SLC2A12 (GLUT12). GLUT12 is important for glucose uptake and subsequent cellular proliferation. Taken together, AR signaling cascades were demonstrated to work in concert with additional oncogenic pathways to augment multiple aspects of glucose metabolism for the purposes of supporting the energetic and biosynthetic needs of prostate cancer cells. As such, I propose targeting these newly identified metabolic pathways may offer a new therapeutic approach for the diagnosis and/or treatment of advanced prostate cancer.

Description

Keywords

Prostate cancer, Pentose phosphate pathway, Glycolysis, Glucose transporters, AMPK, CaMKK2, PPP, G6PD, PFKFB2, PFKFB3, MTOR, GLUT12, TBC1D4

Citation

Portions of this document appear in: Tsouko, E., A. S. Khan, M. A. White, J. J. Han, Y. Shi, F. A. Merchant, M. A. Sharpe, L. Xin, and Daniel E. Frigo. "Regulation of the pentose phosphate pathway by an androgen receptor–mTOR-mediated mechanism and its role in prostate cancer cell growth." Oncogenesis 3, no. 5 (2014): e103-e103.