Src-Induced cisplatin resistance mediated by cell-to-cell communication.
Cisplatin-induced cell death can be triggered by cell-to-cell communication through gap junctions. Here, we show that activated src produces tyrosine phosphorylation of the gap junction protein connexin 43, decreases gap junction communication, and increases cell survival in response to cisplatin. Experiments with mixed cell populations show that src activity in one cell can confer increased cisplatin survival on neighboring cells, even when the neighboring cells lack such src activity. This work is the first demonstration that expression of an oncogene in one cell can affect the survival of a neighboring cell not expressing the oncogene in response to a chemotherapeutic drug. The trans-acting effect of activated src on neighboring cells can be blocked by inhibitors of src kinase or by siRNA-mediated knockdown of src expression, and it can be counteracted by forced up-regulation of connexin 43, via either gene transfer or proteasome inhibition. These results identify a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Elizabeth
E
Peterson-Roth
Cathleen M
CM
Brdlik
Peter M
PM
Glazer
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology*; D018031:Connexin 43 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics
D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D018031:Connexin 43; D004268:DNA-Binding Proteins; C500216:GJA1 protein, human; D034741:RNA, Small Interfering; D015688:Oncogene Protein pp60(v-src); C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D002945:Cisplatin