Relationships between proto-oncogene expression and apoptosis induced by anticancer drugs in human prostate tumor cells.
A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (> 10-fold) to several clinically active anticancer drugs, including VP-16 and cisplatin. Previous studies showed that resistance to these drugs was not due to expression of the mdr1 gene, or modifications in topoisomerases but may have resulted from high expressions of certain proto-oncogenes (Yamazaki et al. (1994) Biochim. Biophys. Acta 1226, 89-96). Flow cytometry, DNA gel electrophoresis and northern blot analysis were used to further characterize drug responses in sensitive and resistant cells. Treatment of the sensitive PC3 cells with VP-16 and CDDP resulted in accumulation of cells in S and G2, and G1 and S phases, respectively, and caused significant degradation of the genomic DNA into internucleosomal sized DNA fragments, indicating apoptosis. In contrast, resistant PC3 cells showed little or no DNA fragmentation. Resistant PC3(R) cells expressed 2-3-fold more bcl2 protein than the parental PC3 cells, and overexpressed c-myc, c-jun and H-ras mRNA compared to sensitive cells. Treatment with VP-16 or CDDP significantly induced c-myc mRNA levels in sensitive PC3 cells. H-ras message was not affected by either VP-16 or CDDP treatment in PC3 cells. These studies, taken together, suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to altered levels of bcl2 and/or oncogene overexpression in PC3(R) cells.
Sinha
B K
BK
Biochemical and Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Yamazaki
H
H
Eliot
H M
HM
Schneider
E
E
Borner
M M
MM
O'Connor
P M
PM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide; D002945:Cisplatin