Molecular mechanisms of differential response to anticancer drugs

Description of projects available to graduate students:
The immediate goal of our research is to understand how anticancer drugs kill cancer cells, and more importantly, why they fail so often. In the long term, we will attempt to use this knowledge to identify novel molecular targets and treatment strategies to improve cancer chemotherapy and chemoprevention.

We have used a combination of molecular and genetic approaches to study how cell death regulators modulate drug sensitivity. We identified a potent apoptosis inducer called PUMA, which functions as a key regulator of apoptosis induced by conventional and targeted anticancer drugs. We have also studied the role of SMAC/Diablo, a mitochondrial apoptogenic protein, in the killing of cancer stem cells by chemopreventive drugs. Furthermore, our recent data reveal that regulators of non-apoptotic cell death, such as the autophagy inducer Beclin 1 and the necrosis regulator RIPK3, contribute to differential chemotherapeutic response.

The specific projects in our lab are focused on four areas: (1) understand how PUMA, SMAC, and other cell death regulators modulate chemotherapeutic response; (2) determine how targeted anticancer drugs kill human cancer cells; (3) delineate the role of cancer stem cell in cancer chemoprevention; and (4) identify novel small molecules to target cell death regulators to improve chemotherapy and chemoprevention.

For more information about our research, please visit:
http://www.pharmacology.us/Faculty/LinZhang
http://myprofile.cos.com/zhangli

Representative Publications
Li, H., Wang, P., Sun, Q., Ding, W.X., Yin, X.M., Sobol, R.W., Stolz, D.B., Yu, J., and Zhang, L. (2011) Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase-8-mediated cleavage of Beclin 1. Cancer Research 71:3625-3634.
Qiu, W.*, Wu, B.*, Wang, X., Buchanan, M., Regueiro, M.D., Hartman, D., Schoen, R.E., Yu, J. and Zhang, L. (2011) PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. Journal of Clinical Investigation 121: 1722–1732.
Qiu, W., Wang, X., Leibowitz, B., Liu, H., Barker, N., Okada, H., Oue, N., Yasui W., Clevers, H., Schoen, R.E., Yu, J. and Zhang, L. (2010) Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc. Natl. Acad. Sci. USA. 107: 20027-20032.
Bank, A., Wang, P., Du, C.Y., Yu, J., and Zhang, L. (2008) SMAC mimetics sensitize nonsteroidal anti-inflammatory drug-induced apoptosis by promoting caspase-3-mediated cytochrome c release. Cancer Research 68: 276-284. (A Bank was a Ph.D. student in the lab)
Zhang, L., Yu, J., Park, B.H., Kinzler, K.W. and Vogelstein, B. (2000) Role of BAX in the apoptotic response to anti-cancer agents. Science 290: 989-992.

Techniques graduate student will learn:
Cell culture, molecular cloning, apoptosis assay, cell cycle analysis, DNA, RNA and protein analysis, gene-targeting, RNAi, analysis of intestinal stem cells, analysis of animal tissues, assay development for library screening