Abstract
The c‐Myc transcription factor is a key regulator of cell proliferation, differentiation, and apoptosis. While deregulation of myc induces programmed cell death, defects in the apoptotic program facilitate Myc‐driven tumor development. We have treated c‐Myc inducible mouse cells and rat fibroblasts with different c‐myc status with cytotoxic drugs to explore the effect of c‐Myc on drug‐induced apoptosis. We found that c‐Myc overexpression potentiated etoposide‐, doxorubicin‐, and cisplatin‐induced cell death in mouse fibroblasts. In addition, these drugs provoked a strong apoptotic response in c‐Myc‐expressing cells, but a weak apoptosis in c‐myc null Rat1 cells. In contrast, staurosporine‐induced apoptosis was c‐Myc‐independent, confirming a functional apoptotic pathway in c‐myc null cells. Apoptosis was paralleled by c‐Myc‐dependent Bax‐activation after etoposide and doxorubicin treatment, but not after cisplatin administration. All three drugs induced higher caspase activation in c‐Myc expressing cells than in c‐myc null cells. Furthermore, etoposide treatment of c‐Myc expressing cells resulted in PKCδ cleavage, while inhibition of PKCδ reduced etoposide‐induced apoptosis and prevented Bax activation. Taken together, these findings suggest that Bax and caspase activation, together with PKCδ signaling are involved in c‐Myc‐dependent etoposide‐induced apoptosis. © 2006 Wiley‐Liss, Inc.