Cisplatin-induced activation of the EGF receptor

Moran Benhar, David Engelberg, Alexander Levitzki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

Cisplatin (CDDP) is an efficient DNA-damaging anti-tumor agent employed for the treatment of various human cancers. CDDP activates nuclear as well as cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage repair and programmed cell death. Here we report that CDDP also activates a membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show that EGFR is activated in response to CDDP in various types of cells that overexpress the receptor, including transformed human glioma cells and human breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead receptor. We also show that CDDP-induced EGFR activation is independent of receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP-iuduced EGFR activation. We propose that EGFR activation in response to CDDP is a survival response, since inhibition of EGFR activation enhances CDDP-induced death. These findings show that signals generated by DNA damage can modulate EGFR activity, and argue that interfering with CDDP-induced EGFR activation in tumor cells might be a useful approach to sensitize these cells to genotoxic agents.

Original languageAmerican English
Pages (from-to)8723-8731
Number of pages9
JournalOncogene
Volume21
Issue number57
DOIs
StatePublished - 12 Dec 2002

Bibliographical note

Funding Information:
This study was supported by the Ministry of Science of the state of Israel and by the Israel Cancer Association through the estate of the late Alexander Smidoda.

Keywords

  • Cisplatin
  • DNA damage
  • EGF receptor
  • Glioblastoma
  • Src

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