Role of PARP cleavage in apotosis caused by acidic stress.

초록

It has been known that tumor cells undergo apoptosis when they are exposed to acidic environment or they are treated with agent which lower the intracellular pH (pHi). The mechanisms for the induction of apoptosis deu to low pHi has been unclear. When the pHi of HL-60 huuman leukemia cells were lowed to 6.8-7.1 range by incibatingthe cells in acidic medium the cells underwent apoptosis as judged from DNA fragmentation , PARP cleavage and flow cytometric determination of cells with sun-G1 DNA content. Preteatment of cells with inhibitors specific for ICE (Ac-YVAD-H) or CPP32 (Ac-DEVAD-H) prevented the acidic stress-induced PARP cleavage and DNA fragmentation,. This result unequivocally demonstratrated that acidic stress activated the caspases thereby causing PARP cleavage followed by DNA fragmentation. The observation that inhibition of either ICE or CPP32 could inhivit acidic stress-inhibit acidic stess-induced apoptosis suggested that ICE activates pro-CPP32, which then cleaves PARP. The occurrence of apoptosis in an acidic environment may havee a significant implication in the tumor cell proliferation since the intratumor rnvironment is acidic with pH as low as 6.0. Supported by NCI grant CA13353 and ACS Institutional Grant/IRG-01.