title: Src inhibits adriamycin-induced senescence and G2 checkpoint arrest by blocking the induction of p21waf1.
abstract: 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.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U564, Cancer Center Paul Papin, Angers, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Vigneron
authors.forename: Igor B
authors.initials: IB
authors.lastname: Roninson
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.forename: Olivier
authors.initials: O
authors.lastname: Coqueret
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008938:Mitosis / Q000502:physiology; D011123:Polyploidy; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019061:src-Family Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C107961:ZBTB17 protein, human; D004317:Doxorubicin; D019061:src-Family Kinases