Yunfeng Zhao, PhD
Associate Professor of Pharmacology, Toxicology & Neuroscience
Major Research Interests
- PKM2 inhibition and redox regulation in chemoprevention.The major goal of this project is to determine whether inhibition of pyruvate kinase M2 (PKM2), the enzyme in the last step of glycolysis, can serve as a novel approach for cancer prevention. Up-regulation of PKM2 has been reported in many types of human cancers, however, at what stage of cancer development PKM2 is activated, and whether oxidative stress, as a contributing factor to cancer, plays an important role in PKM2 activation are unclear. Our initial studies showed that both UV irradiation and tumor promoters altered cellular metabolism via up-regulating PKM2 and down-regulating the M1 isoform of PKM (PKM1). This M1→M2 shift has been observed in various human cancers; however, it has not been reported in the early stage of cancer development. In addition, many carcinogens are known to induce oxidative stress and overexpression of manganese superoxide dismutase (MnSOD) suppresses cancer development in many cancer models. Therefore, we hypothesize that PKM2 activation is a tumor promoting event during early cancer development and oxidative stress is conducive to PKM2 activation. We will test this hypothesis by applying specific PKM2 inhibitors in a chemically induced skin carcinogenesis mouse model
- To study the molecular mechanisms of mitochondrial uncoupling in cancer development. Most of the normal cell’s energy is synthesized in mitochondria in the form of ATP. However, not all of the energy available in the electrochemical gradient is coupled to ATP synthesis. Some of the energy is consumed by “proton leak” reactions. The nonproductive proton leak termed mitochondrial uncoupling is physiologically important and accounts for 20-25% of basal metabolic rate. The impact of mitochondrial uncoupling on cellular physiology is not restricted to normal cells. Mitochondrial uncoupling also plays an important role in the reprogramming of cancer cell metabolism. Mitochondrial uncoupling has been suggested to have a natural antioxidant effect that increases respiratory rates and thus attenuates free radical generation. It is not surprising that high levels of mitochondrial uncoupling are found in various chemoresistant cancer cell lines, which may provide a prosurvival advantage to tumor cells. Our studies have shown that mitochondrial uncoupling also blocks p53 mitochondrial translocation. p53, the most known tumor suppressor, can initiate apoptosis in response to cellular stress stimuli. Our studies suggest that p53 and mitochondrial uncoupling are contradictory during apoptosis. We are studying the interactions between p53 and mitochondrial uncoupling using cell transformation models and mitochondrial uncoupled human cancer cells.
Selected recent publications
- Robbins D, Zhao, Y. Manganese superoxide dismutase in cancer prevention. Antioxid Redox Signal. 20(10):1628-45, 2014.
- Li W, Liu J, Zhao Y. PKM2 Inhibitor Shikonin Suppresses TPA-induced Mitochondrial Malfunction and Proliferation of Skin Epidermal JB6 Cells. Mol Carcinog. 53(5):403-12, 2014.
- Li W, Zhao Y. Withaferin A Suppresses Tumor Promoter TPA-induced Decreases in IDH1 Activity and Mitochondrial Function in Skin Epidermal JB6 Cells. Cancer Sci. 104:143-8, 2013.
- Robbins D, Ponville J, Morris K, Zhao Y. Involvement of PTEN in TPA-mediated p53-activation in mouse skin epidermal JB6 cells. FEBS Lett, 586: 4108-13, 2012.
- Robbins D, Wittwer JA, Codarin S, Circu M, Aw TK, Huang TT, VanRemmen H, Richardson A, Wang DB, Witt SN, Klein RL, Zhao Y. IDH1 Is Downregulated during Early Skin Tumorigenesis Which Can Be Inhibited by Overexpression of MnSOD. Cancer Sci. 103: 1429-33, 2012.
- Li W, Zhao Y. Warburg Effect and Mitochondrial Metabolism in Skin Cancer. J Carcinogene Mutagene. Accepted. Review.
- Wittwer JA, Robbins D, Wang F, Codarin S, Shen X, Kevil C, Huang TT, Remmen H, Richardson A, Zhao Y. Enhancing Mitochondrial Respiration Suppresses Tumor Promoter TPA Induced PKM2 Expression and Cell Transformation in Skin Epidermal JB6 Cells. Cancer Prev Res 4: 1476-84, 2011.
- Wang F, Liu J, Robbins D, Morris K, Sit A, Liu YY, Zhao Y. Mutant p53 exhibits trivial effects on mitochondrial functions which can be reactivated by ellipticine in lymphoma cells. Apoptosis. 16: 301-10, 2011.
- Wang F, Fu X, Chen X, Chen X, Zhao Y. Mitochondrial uncoupling inhibits p53 mitochondrial translocation in TPA-challenged skin epidermal JB6 cells. PLoS One. 5: e13459, 2010.
- Robbins D, Gu X, Shi R, Liu J, Wang F, Ponville J, McCord JM, Zhao Y. The chemopreventive effects of Protandim: modulation of p53 mitochondrial translocation and apoptosis during skin carcinogenesis. PLoS One 5: e11902, 2010.
- Liu J, Gu X, Robbins D, Li G, Shi R, McCord JM, Zhao Y. Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model. PLoS One 4: e5284, 2009.
- Liu J, St. Clair DK, Gu X, Zhao Y. Blocking mitochondrial permeability transition prevents p53 mitochondrial translocation during skin tumor promotion. FEBS Lett. 582: 1319-1324, 2008.
Graduate students interested in cancer metabolism research feel free to contact Dr. Zhao at firstname.lastname@example.org
Undergraduate research opportunities
Positions for undergraduate research internship may be available during the summer.
Medical students interested in basic cancer research feel free to stop by Dr. Zhao’s office (5-221) to discuss your interests.