Elucidating the Role of Glucose Metabolism in Prostate Cancer

dc.contributor.advisorFrigo, Daniel E.
dc.contributor.committeeMemberWilliams, Cecilia M.
dc.contributor.committeeMemberZhang, Xiaoliu Shaun
dc.contributor.committeeMemberMcGuire, Sean E.
dc.creatorCuko, Efrosini 1987-
dc.date.accessioned2019-11-12T03:04:57Z
dc.date.available2019-11-12T03:04:57Z
dc.date.createdDecember 2015
dc.date.issued2015-12
dc.date.submittedDecember 2015
dc.date.updated2019-11-12T03:04:57Z
dc.description.abstractProstate 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.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.citationPortions 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.
dc.identifier.urihttps://hdl.handle.net/10657/5371
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. UH Libraries has secured permission to reproduce any and all previously published materials contained in the work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectProstate cancer
dc.subjectPentose phosphate pathway
dc.subjectGlycolysis
dc.subjectGlucose transporters
dc.subjectAMPK
dc.subjectCaMKK2
dc.subjectPPP
dc.subjectG6PD
dc.subjectPFKFB2
dc.subjectPFKFB3
dc.subjectMTOR
dc.subjectGLUT12
dc.subjectTBC1D4
dc.titleElucidating the Role of Glucose Metabolism in Prostate Cancer
dc.type.dcmiText
dc.type.genreThesis
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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