c-Myc-dependent etoposide-induced apoptosis involves activation of Bax and caspases, and PKCdelta signaling.
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 PKCdelta cleavage, while inhibition of PKCdelta reduced etoposide-induced apoptosis and prevented Bax activation. Taken together, these findings suggest that Bax and caspase activation, together with PKCdelta signaling are involved in c-Myc-dependent etoposide-induced apoptosis.
Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Ami
A
Albihn
Jakob
J
Lovén
Johan
J
Ohlsson
Lyda M
LM
Osorio
Marie
M
Henriksson
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D019384:Nucleic Acid Synthesis Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D018124:Receptors, Tumor Necrosis Factor; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D004317:Doxorubicin; D051745:Protein Kinase C-delta; D020169:Caspases; D002945:Cisplatin