The effect of exposure to low extracellular pH on heat-induced apoptosis in human cells
The molecular chaperone protein Hsp70 (heat-shock protein 70) plays essential roles in the regulation of protein folding and is a potent inhibitor of stress-induced apoptosis. This protein is often overexpressed in tumor cells and may be a contributing factor in tumorigenesis through apoptosis suppression. Conditions that affect the ability of Hsp70 to suppress apoptosis could provide novel strategies for cancer treatment. This thesis describes experiments that examined the effect of reduced extracellular pH, as occurs in tumors, on heat-induced apoptosis in a human acute lymphoblastic T cell line (PEER) that was engineered to inducibly express Hsp70. Decreased pH in the range of 7.4 to 6.0 reduced the extent of cell death in heat-stressed cells (43°C/1hr). This was correlated with reduced activation of the c-jun N-terminal kinase (JNK). The ability of Hsp70 to block heat-induced JNK activation and apoptosis was impaired at low pH suggesting that manipulation of tumor cell pH might be an effective means to prevent suppression of apoptosis by Hsp70.