The Zhang lab studies the molecular mechanisms of apoptosis induced by anti-cancer agents. Common epithelial malignancies, including cancers of breast, colon and lung, are often resistant to standard treatments such as chemotherapy and irradiation. We are investigating how apoptosis regulators, including PUMA, Bax and SMAC/Diablo, mediate apoptosis induced by anticancer agents, and whether deregulation of these proteins contributes to acquired resistance to anticancer agents. We identified PUMA as a BH3-only Bcl-2 family protein that plays an essential role in DNA damage-induced and p53-dependent apoptosis. We also found that the proapoptotic Bcl-2 family protein BAX and the mitochondrial apoptogenic protein SMAC/Diablo mediate apoptosis induced by NSAIDs (non-steroidal anti-inflammatory drugs), which have been used for chemoprevention of colon cancer. Efforts are currently undertaken to restore apoptosis regulation in human cancer cells by modulating these proteins. The long-term goal of our research is to develop improved strategies and novel agents for chemotherapy and chemoprevention of human cancer.
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.
Cell death in anticancer therapies
Our research program has centered on several molecules that control discrete steps of programmed cell death. The first one, PUMA, is a downstream target of the tumor suppressor p53 and a BH3-only Bcl-2 family protein. PUMA is required for DNA damage-induced and p53-dependent apoptosis, and also plays a key role in apoptosis induced by several targeted anticancer drugs. The second one, SMAC, is a mitochondrial apoptogenic protein and a caspase activator. SMAC helps to execute apoptosis induced by anticancer drugs via a mitochondrial feedback loop. Regulators of non-apoptotic cell death, such as the autophagy inducer Beclin 1 and the necrosis regulator RIPK3, have also been studied. Through analyses of these molecules and their associated protein networks, we try to gain deep understanding on how cell death is initiated and executed in human cancer cells, why some cancer cells are not sensitive to anticancer drugs, and what can be done to restore their sensitivity.
Oncogenic stem cells as the target of cancer chemoprevention
Prevention of human cancer through the use of chemical agents such as non-steroidal anti-inflammatory drugs (NSAIDs) has emerged as a promising strategy to reduce morbidity and mortality of cancer. Our recent studies showed that intestinal stem cells that have acquired oncogenic alterations are targeted by NSAIDs in chemoprevention of colon cancer. We are investigating how NSAIDs trigger apoptosis in such oncogenic stem cells, and if induction of apoptosis is critical for the chemopreventive effects of NSAIDs. We will also determine if apoptosis regulators can be used as markers to predict outcomes of chemoprevention of cancer patients, and if manipulation of apoptosis regulators can be used to improve the chemopreventive effects of NSAIDs.
Manipulation of cell death regulators
To target PUMA, we have developed a high-throughput screening system for identifying small molecules that can activate PUMA in p53-deficient cancer cells. In collaboration with the Pittsburgh Drug Discovery Institute, we will screen compound libraries to identify novel PUMA inducers. We have also identified and characterized small molecules that mimic the functional domains of PUMA and SMAC. Efforts are undertaken to apply these small molecules to chemotherapy and chemoprevention.
Fu L, Li L, Wang J, Knickelbein K, Zhang L, Milligan I, Xu Y, O'Hara K, Bitterman L, Du W. Synthesis of clickable amphiphilic polysaccharides as nanoscopic assemblies. Chem Commun (Camb). 2014 Oct 28;50(84):12742-5. doi: 10.1039/c4cc06343k. PubMed PMID: 25204678.