Hsp60 Regulation of Tumor Cell Apoptosis*

  1. Jagadish C. Ghosh,
  2. Takehiko Dohi,
  3. Byoung Heon Kang and
  4. Dario C. Altieri1
  1. Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachustetts 01605
  1. 1 To whom correspondence should be addressed: Dept. of Cancer Biology, LRB428, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-5775; Fax: 508-856-5791; E-mail: dario.altieri{at}umassmed.edu.

Abstract

Molecular chaperones may promote cell survival, but how this process is regulated, especially in cancer, is not well understood. Using high throughput proteomics screening, we identified the cell cycle regulator and apoptosis inhibitor survivin as a novel protein associated with the molecular chaperone Hsp60. Acute ablation of Hsp60 by small interfering RNA destabilizes the mitochondrial pool of survivin, induces mitochondrial dysfunction, and activates caspase-dependent apoptosis. This response involves disruption of an Hsp60-p53 complex, which results in p53 stabilization, increased expression of pro-apoptotic Bax, and Bax-dependent apoptosis. In vivo, Hsp60 is abundantly expressed in primary human tumors, as compared with matched normal tissues, and small interfering RNA ablation of Hsp60 in normal cells is well tolerated and does not cause apoptosis. Therefore, Hsp60 orchestrates a broad cell survival program centered on stabilization of mitochondrial survivin and restraining of p53 function, and this process is selectively exploited in cancer. Hsp60 inhibitors may function as attractive anticancer agents by differentially inducing apoptosis in tumor cells.

Footnotes

  • 2 The abbreviations used are: Hsp, heat shock protein; siRNA, small interfering RNA; WT, wild type; CCCP, carbonyl cyanide p-chlorophenylhydrazone; GST, glutathione S-transferase; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.

  • * This work was supported by National Institutes of Health Grants CA78810, CA90917, and HL54131 (to D. C. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received July 18, 2007.
    • Revision received December 17, 2007.
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