Multiple classes of chemotherapeutic drugs work by inducing cancer cell death, but these drugs are often ineffective in treating cancer patients. Dr. Lin Zhang, Professor of Pharmacology and Chemical Biology, seeks to improve treatment outcome by studying the mechanisms underlying both drug-mediated cytotoxicity and cancer cell resistance to these drugs.
The Zhang laboratory is particularly interested in PUMA (p53 upregulated modulator of apoptosis), a protein upregulated by multiple anticancer drugs that promotes programmed cell death, otherwise known as apoptosis. In a paper recently published in the Proceedings of the National Academy of Sciences, they showed that PUMA also plays a key role in enhancing necroptosis, a type of programmed necrotic cell death associated with inflammation. In their study, stimulation of necroptosis in cancer cells led to upregulated PUMA expression, triggering release of mitochondrial DNA into the cytosol and further necroptotic cell death in a positive feedback loop. Unlike apoptosis, necroptosis engages the immune system to eliminate dead cell debris. Thus, PUMA has the potential to both amplify the death signal and to promote cancer immunity. Dr. Zhang hopes to build upon this work to improve cancer therapy and develop PUMA as a biomarker for treatment response.