Date of Award
Master of Science
Jennifer A. Doll
Jennifer A. Doll, Jeri-Anne Lyons, Dean T. Nardelli
High Fat Diet, Metformin, Obesity, Oleic Acid, Prostate Cancer, Prostate Cancer Cell Lines
Prostate cancer (PCa) is one of the most common cancers in American males. A high fat diet and obesity accelerate PCa progression and increase the 1risk of death from disease. Epidemiological studies have indicated that PCa patients with type 2 diabetes have higher mortality rates than PCa patients without diabetes. Type 2 diabetics who are on metformin, a drug to control blood sugar levels, show a delay in PCa progression in comparison with PCa patients with type 2 diabetes who are not on metformin. It has been proposed that metformin inhibits proliferation via activation of AMP-activated protein kinase (AMPK) or by blocking proliferation at the G0/G1 phase in the cell cycle with a reduction in cyclin D1. However, the mechanism is still unclear, as these in vitro studies used 5 mM metformin which is physiologically not attainable. AMPK is known to stimulate lipolysis, the breakdown of triglycerides into fatty acids functions. As increased lipid anabolism is known to promote PCa, the lipolysis produced by AMPK, during metformin treatment, may also contribute to the anti-tumor activity of metformin.
Pigment epithelium-derived factor (PEDF) is a glycoprotein with multiple functions. Its expression is decreased in many cancer types, including PCa. Exogenous PEDF treatment reduces prostate tumor growth, metastasis, and angiogenesis. Interestingly, it has been reported that type 2 diabetes patients on metformin present with higher serum levels of PEDF in comparison with healthy patients not on metformin.
In this work, I tested the hypothesis that one mechanism of metformin's activity may be via stimulation of PEDF. Metformin increased intracellular PEDF in LNCaP cells, and extracellular PEDF in RWPE-1 and LNCaP cells. Metformin also reduced cell proliferation and increased lipolysis in PCa cells at physiological obtainable doses (0.02 and 0.5 mM). I also observed that at these lower doses, metformin increased the expression of cyclin D1 and AMPK, but at 5 mM doses reduced cyclin D1. Supporting PEDF's role in lipid metabolism, in PEDF KO prostate tissues there was less lipolytic activity and altered triglyceride levels in comparison with wild type tissue. Overall, these data support the hypothesis that metformin may act through PEDF.
Tolentino, Miguel Angel, "Metformin-Induced PEDF Expression Regulates Cell Proliferation and Lipid Metabolism in Prostate Cancer Cells" (2013). Theses and Dissertations. 335.