Camptothecin-induced apoptosis is enhanced by Myc and involves PKCdelta signaling.
The MYC oncogene is frequently deregulated in human tumors, indicative of a poor prognosis because of enhanced resistance to treatment. In such cases, the cellular sensitivity to chemotherapy could be restored by reactivation of Myc-driven apoptosis. We have analyzed apoptosis induced by the cytotoxic agents camptothecin (CPT) and paclitaxel (PTX) using Rat1 fibroblasts with different c-myc status and human Tet21N neuroblastoma cells with conditional MYCN expression. In these cell lines, the drug sensitivity was enhanced by Myc in line with previous reports showing that Myc sensitizes to apoptosis induction by many different apoptosis inducers. CPT-induced apoptosis involved cleavage and activation of proapoptotic Bid and Bax, induction of mitochondrial membrane depolarization, activation of caspase-9 and caspase-3, protein kinase c delta (PKCdelta) signaling and upregulation of p53. We also observed reduced transcriptional activity by Myc and other transcription factors in response to CPT. In contrast, the manner by which Myc potentiates the apoptosis induced by PTX differs from that of CPT and remains to be explored. In summary, our findings revealed that activation of PKCdelta in response to CPT treatment requires Myc and is important in CPT-mediated apoptosis signaling.
Albihn
Ami
A
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Mo
Hao
H
Yang
Ying
Y
Henriksson
Marie
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D016259:Genes, myc; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel; D002166:Camptothecin