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RESEARCH PAPER
1 Apoptosis Department and 2 Danish Centre for Translational Breast Cancer Research, Institute for Cancer Biology, Danish Cancer Society, 2100 Copenhagen, Denmark; 3 Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy; 4 Biotech Research and Innovation Centre, 2100 Copenhagen, Denmark
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: Heat-shock proteins 70; macrophage inhibitory cytokine-1; neoplasms; senescence; RNA interference; microarray]
Received November 11, 2004; revised version accepted December 23, 2004.
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.
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