Major Research Interests

1. 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
2. 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.

PEER-REVIEWED PUBLICATIONS

(selected from 68 papers)

1. Yu J, Shi L, Lin W, Lu B, Zhao Y. UCP2 promotes proliferation and chemoresistance through regulating the NF-κB/β-catenin axis and mitochondrial ROS in gallbladder cancer. Biochem Pharmacol. 2020;172:113745.
2. Li J, Jia Y, An L, Niu C, Cong X, Zhao Y. Uncoupling protein 2 is upregulated in melanoma cells and contributes to the activation of Akt/mTOR and ERK signaling. Int J Oncol. 2020 Mar 12.
3. Li J, Jiang R, Cong X, Zhao Y. The role of UCP2 gene polymorphisms in obesity and diabetes and the role of UCP2 in cancer. FEBS Lett. 2019; 593:2525-2534.
4. Yu, J, Shi L, Shen X, Zhao, Y. UCP2 regulates cholangiocarcinoma cell plasticity via mitochondria-to-AMPK signals. Biochem Pharmacol. 166:174-184, 2019.
5. Sreedhar A, Cassel T, Smith P, Lu D, Hyung NW, Lane AN, Zhao Y. UCP2 overexpression redirects glucose into anabolic metabolic pathways. Proteomics, 2018; 19:e1800353.
6. Sreedhar A, Li J, Zhao Y. Next-Gen therapeutics for Skin Cancer: Nutraceuticals. Nutrition & Cancer, 2018; 70:697-709.
7. Sreedhar A, Petruska P, Miriyala S, Panchatcharam M, Zhao Y. UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation. Oncotarget. 2017;8:95504-95515.
8. Sreedhar A, Lefort J, Petruska P, Gu X, Shi R, Miriyala S, Panchatcharam M, Zhao Y. UCP2 Upregulation Promotes PLCγ-1 Signaling During Skin Cell Transformation. Mol Carcinog. 2017;56:2290-2300.
9. Sreedhar A, Zhao Y. Uncoupling protein 2 and metabolic diseases. Mitochondrion. 2017;34:135-140. Review.
10. Li W, Zhang C, Du H, Huang V, Sun B, Harris JP, Richardson Q, Shen X, Jin R, Li G, Kevil CG, Gu X, Shi R, Zhao Y. Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model. Mol Carcinog. 2016;55:1739-1746.
11. Li W, Zhang C, Ren A, Li T, Jin R, Li G, Gu X, Shi R, Zhao Y. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation. PLoS One. 2015;10:e0126459.
12. Li W, Zhang C, Jackson K, Shen X, Jin R, Li G, Kevil CG, Gu X, Shi R, Zhao Y. UCP2 knockout suppresses mouse skin carcinogenesis. Cancer Prev Res 2015 Jun;8(6):487-91.

Lauren Pilcher (Student Worker)

Graduate Students

Graduate students interested in cancer metabolism research feel free to contact Dr. Zhao at yzhao1@lsuhsc.edu

Undergraduate research opportunities

Positions for undergraduate research internship may be available during the summer.

Medical students

Medical students interested in basic cancer research feel free to stop by Dr. Zhao’s office (5-221) to discuss your interests.