Inhibition of pp60(c-Src) reduces Bcl-X(L) expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors

Rotem Karni, Richard Jove, Alexander Levitzki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

Tumors that overexpress HER-2/neu receptor or exhibit enhanced EGFR signaling have been reported to possess constitutively activated Src family kinases, especially pp60(c-Src). High levels of pp60(c-Src) activity have also been reported for cell lines that overexpress the EGFR or the chimeric EGFR-HER-2 receptor. It has therefore been suggested that Src kinases may contribute significantly to the oncogenic phenotype of these cells and to the degree of malignancy of tumors that overexpress EGFR family receptors. In this study we show that the induced expression of c-SRC antisense RNA or the application of a selective Src kinase inhibitor induces growth arrest, programmed cell death and reverses the transformed properties of cells that overexpress EGFR or HER-2 receptors. We show that inhibition of Src kinase expression or activity results in the reduction of Stat3 tyrosine phosphorylation, decline of Bcl-X(L) expression, and induction of cell death. Using a construct in which the promoter of Bcl-X, which possesses putative Stat3 sites, is tethered to the luciferase reporter gene, we show that inhibition of Src activity or expression induces a decline in Bcl-X expression. We also show that the expression of activated Src induces activation of the Bcl-X promoter. This activation is inhibited by the expression of kinase dead Src or of Stat3β, the dominant-negative form of Stat3. Taken together, these results support the hypothesis that Src positively regulates the transformed phenotype of cells overexpressing EGFR family kinases. Furthermore, these results also suggest that Src positively regulates Bcl-X(L) expression via Stat3 activation and thus acts not only as a potent mitogenic signaling element, but also as an anti-apoptotic signaling protein. The combination of both activities probably confers upon activated Src its oncogenic activity. Since Src kinase is activated in many tumors, pp60(c-Src) kinase inhibitors may prove useful as anti-cancer agents for many types of cancer.

Original languageAmerican English
Pages (from-to)4654-4662
Number of pages9
JournalOncogene
Volume18
Issue number33
DOIs
StatePublished - 19 Aug 1999

Bibliographical note

Funding Information:
We would like to thank Dr Ricardo Martinez from SUGEN, Inc. for providing us with the mouse SRC cDNA. We also thank Dr Shoshana Klein and Dr Allan Bar-Sinai from our laboratory for their help preparing the manuscript. This study was partially supported by The James S McDonnel Foundation (USA) and partially by The Israel Science Foundation of the Israel Academy of Sciences and Humanities, Jerusalem, Israel.

Keywords

  • Bcl-X
  • EGFR
  • HER-2
  • c-Src

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