Like yoga for office drones, cells do have coping strategies for stress. Heat, lack of nutrients, oxygen radicals – all can wreak havoc on the delicate internal components of a cell, potentially damaging it beyond repair. Proteins called HSPs (heat shock proteins) allow cells to survive stress-induced damage. Scientists have long studied how HSPs work in order to harness their therapeutic potential. Donna George, PhD, Associate Professor of Genetics, and Julie Leu, PhD, Assistant Professor of Genetics, both at the University of Pennsylvania School of Medicine, in collaboration with the lab of Maureen Murphy, PhD at Fox Chase Cancer Center, identified a small molecule that inhibits the heat shock protein HSP70. They also showed that the HSP inhibitor could stop tumor formation and significantly extend survival of mice. They describe their findings in this month's issue of Molecular Cell. HSP70 is an intracellular quality control officer, refolding misfolded proteins and preventing protein aggregation, which among other disorders, is associated with neurodegenerative diseases. HSP70 also ferries proteins to their proper intracellular locations. Tumor cells, which face an abundance of cellular stresses, typically overexpress HSP70, making it a potentially interesting anticancer target. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that promote protein misfolding. HSP70 helps cancer cells deal with this stress. Unlike normal cells, which typically express little, if any, of HSP70, cancer cells contain high levels of this protein all of the time. Indeed, HSP70 has been termed a cancer-critical survival factor, since cancer cells probably require the actions of this protein to survive the protein-altering adverse conditions. The inhibitor, called PES, interferes with the HSP70 activities that the cancer cell needs to survive, so by targeting HSP70, one can target the cancer cell. The investigators showed that PES interacts with HSP70 by blocking its stress-relieving functions. It also induces HSP70-dependent cell death by disrupting the cell's ability to remove damaged components. Paradoxically for a compound first identified for blocking the cell-death pathway of apoptosis, PES does kill cells, but by a different mechanism.
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