Role of c-myc protein in hormone refractory prostate carcinoma: cellular response to paclitaxel.
Amplification of the c-MYC proto-oncogene is a frequent alteration in hormone refractory prostate carcinomas (HRPC). In an attempt to investigate the role of c-myc in the cellular response to paclitaxel (PTX), we used two HRPC cell lines, DU145 and PC3, characterised by different levels of the protein and by different behaviour in response to taxane. In both cell lines, PTX-induced cell death was a caspase-mediated apoptosis. In DU145 cells, PTX induced an early apoptotic response associated with upregulation of c-myc restricted to the G2/M cell population. This event appeared delayed in the presence of c-myc antisense (AS-c-myc), suggesting an upstream regulation of the protein expression. In addition, the antisense approach provided evidence of an involvement of c-myc in the apoptotic response to the taxane. In contrast, in PC3 cells, the overexpressed c-myc was not modulated by drug-treatment and the addition of AS-c-myc did not affect the cell growth inhibition of PTX. In both cell lines, PTX-induced c-myc phosphorylation was concomitant with the mitotic arrest and not related to the modulation of the activation state of AKT and MAPK kinases. Our data indicate that the cellular response to PTX of HRPC cells can involve c-myc and suggest that its pro-apoptotic role is affected by the genetic background, thus supporting a complex and differentiated HRPC cell response to taxanes.
Cassinelli
Giuliana
G
Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
Supino
Rosanna
R
Zuco
Valentina
V
Lanzi
Cinzia
C
Scovassi
A Ivana
AI
Semple
Sean C
SC
Zunino
Franco
F
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D015870:Gene Expression; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D006728:Hormones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D020169:Caspases; D017239:Paclitaxel