Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

  1. Mikkel Rohde1,5,
  2. Mads Daugaard1,5,
  3. Mette Hartvig Jensen1,
  4. Kristian Helin3,4,
  5. Jesper Nylandsted1, and
  6. Marja Jäättelä1,2,6
  1. 1Apoptosis Department and 2Danish Centre for Translational Breast Cancer Research, Institute for Cancer Biology, Danish Cancer Society, 2100 Copenhagen, Denmark; 3Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy; 4Biotech Research and Innovation Centre, 2100 Copenhagen, Denmark

Abstract

Whereas the stress-inducible heat-shock protein 70 (Hsp70) has gained plenty of attention as a putative target for tumor therapy, little is known about the role of other Hsp70 proteins in cancer. Here we present the first thorough analysis of the expression and function of the cytosolic Hsp70 proteins in human cancer cells and identify Hsp70-2, a protein essential for spermatogenesis, as an important regulator of cancer cell growth. Targeted knock-down of the individual family members by RNA interference revealed that both Hsp70 and Hsp70-2 were required for cancer cell growth, whereas the survival of tumorigenic as well as nontumorigenic cells depended on Hsc70. Cancer cells depleted for Hsp70 and Hsp70-2 displayed strikingly different morphologies (detached and round vs. flat senescent-like), cell cycle distributions (G2/M vs. G1 arrest) and gene expression profiles. Only Hsp70-2 depletion induced the expression of macrophage inhibitory cytokine-1 that was identified as a target of P53 tumor-suppressor protein and a mediator of the G1 arrest and the senescent phenotype. Importantly, concomitant depletion of Hsp70 and Hsp70-2 had a synergistic antiproliferative effect on cancer cells. Thus, highly homologous Hsp70 proteins bring about nonoverlapping functions essential for cell growth and survival.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.305405.

  • 5 These authors contributed equally to this work.

  • 6 Corresponding author. E-MAIL mj{at}cancer.dk; FAX 45-35257721.

    • Accepted December 23, 2004.
    • Received November 11, 2004.
| Table of Contents

Life Science Alliance