cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway.
cis-Diamminedichloroplatinum(II) (CDDP) is a chemotherapeutic agent known to inhibit DNA, RNA, and protein synthesis. The cytotoxicity of this drug is thought to result from the formation of DNA intrastrand cross-links. The present work demonstrates that treatment of human myeloid leukemia cells (HL-60, U-937, and KG-1) with CDDP is associated with increased expression of the c-jun gene and that this effect is related to activation by a transcriptional mechanism. The results also demonstrate that treatment with CDDP is associated with increases in protein kinase C (PKC) activity. Furthermore, the finding that pretreatment with H7, an inhibitor of PKC, abrogates the effect of CDDP on c-jun expression suggested the involvement of PKC in this process. Down-regulation of PKC by prolonged pretreatment with 12-O-tetradecanoylphorbol-13-acetate was also associated with inhibition of CDDP-induced c-jun expression. The results further demonstrate that there is a temporal relationship between the CDDP-induced increase in c-jun expression and the occurrence of internucleosomal DNA cleavage characteristic of programmed cell death. These findings suggest that c-jun may be involved in the cellular response to DNA-damaging agents, such as CDDP, and that this effect may be mediated by a PKC-dependent pathway.
Rubin
E
E
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Kharbanda
S
S
Gunji
H
H
Weichselbaum
R
R
Kufe
D
D
D000199:Actins / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects*; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D015398:Signal Transduction; D014410:Tumor Stem Cell Assay
D000199:Actins; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D011493:Protein Kinase C; D002945:Cisplatin