Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells

To understand the roles of bcl-2 for the survival of leukemic cells, we con structed human leukemic HL60 transformant lines in which full length bcl-2 antisense message was conditionally expressed by a tetracycline-regulatable expression system. Cell growth was completely inhibited after antisense me ssage induction and massive cell death was induced. Electron microscopic ex aminations show that cells died by autophagy, but not by apoptosis. The mor phology and the function of mitochondria remained intact: neither the reduc tion in mitochondrial membrane potential nor the nuclear translocation of A lF, a mitochondrial protein that translocates to nuclei in cases of apoptos is, was observed. Caspase inhibitors did not rescue bcl-2-antisense-mediate d autophagy. Thus, bcl-2 is essential for leukemic cell survival and its do wn-regulation results in autophagy.