To elucidate mechanism of cell death in response to
hypoxia, we attempted to compare
hypoxia-induced cell death of HepG2 cells with
cisplatin-induced cell death, which has been well characterized as a typical apoptosis. Cell death induced by
hypoxia turned out to be different from
cisplatin-mediated apoptosis in cell viability and cleavage patterns of
caspases.
Hypoxia-induced cell death was not associated with the activation of p53 while
cisplatin-induced apoptosis is p53 dependent. In order to explain these differences, we tested involvement of micro-
calpain and
m-calpain in
hypoxia-induced cell death. Calpains, especially micro-
calpain, were initially cleaved by
hypoxia, but not by
cisplatin. Interestingly, the treatment of a
calpain inhibitor restored PARP cleavage that was absent during
hypoxia, indicating the recovery of activated
caspase-3. The inhibition of calpains prevented proteolysis induced by
hypoxia. In addition,
hypoxia resulted in a
necrosis-like morphology while
cisplatin induced an apoptotic morphology. The
calpain inhibitor prevented necrotic morphology induced by
hypoxia and converted partially to apoptotic morphology with nuclear segmentation. Our result suggests that calpains are involved in
hypoxia-induced cell death that is likely to be necrotic in nature and the inhibition of
calpain switches
hypoxia-induced cell death to apoptotic cell death without affecting cell viability.