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Src Inhibits Adriamycin-Induced Senescence and G₂ Checkpoint Arrest by Blocking the Induction of p21waf1

¹ Institut National de la Sante et de la Recherche Medicale U564, Cancer Center Paul Papin, Angers, France and ² Ordway Research Institute, Albany, New York

Requests for reprints: Olivier Coqueret, Institut National de la Sante et de la Recherche Medicale U564, Cancer Center Paul Papin, 2 rue Moll, 49033 Angers, France. Phone: 33-2-41-35-27-00, ext. 2564; Fax: 33-2-41-48-31-90; E-mail: olivier.coqueret{at}univ-angers.fr.

DNA-damaging drugs stop tumor cell proliferation by inducing apoptosis, necrosis, or senescence. Cyclin-dependent kinase inhibitor p21waf1 is an important regulator of these responses, promoting senescence and preventing aberrant mitosis that leads to cell death. Because tumors expressing oncogenic tyrosine kinases are relatively resistant to DNA-damaging agents, the effects of Src on cellular responses to anticancer drug Adriamycin were investigated. Src expression increased drug survival in HT1080 fibrosarcoma cells, as measured by the colony formation assay, and strongly inhibited Adriamycin-induced senescence. Src also decreased the number of apoptotic cells while increasing the fraction of cells dying through necrosis. In addition, Src inhibited the G₂ and G₁ tetraploidy checkpoints of Adriamycin-treated cells, permitting these cells to proceed into mitosis and subsequently double their DNA content. Inhibition of senescence and G₂-G₁ checkpoints in Src-expressing cells was associated with the failure of these cells to up-regulate p21waf1 in response to Adriamycin. The failure of p21waf1 induction, despite increased expression of p53 and its binding to p21waf1 promoter, was mediated by the up-regulation of c-Myc, a negative regulator of p21waf1 transcription. Conversely, ectopic expression of p21waf1 inhibited Myc transcription in Src-expressing cells, an effect that was associated with the interaction of p21waf1 with the STAT3 transcription factor at the Myc promoter. These results reveal a complex effect of Src on cellular drug responses and provide an explanation for the effect of this oncogene on cellular drug resistance.

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