Src-Induced Cisplatin Resistance Mediated by Cell-to-Cell Communication

Departments of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut

^* To whom correspondence should be addressed. E-mail: Peter.Glazer{at}yale.edu.

	Abstract

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. [Cancer Res 2009;69(8):3619–24]

Key Words: cisplatin, gap junctions, activated src, connexin 43