Heat Shock Protein May Be Target for Chemotherapy

Cancer researchers have identified an extracellular form of the heat shock protein 90 (hsp90), which has been linked to tumor cell invasiveness, that differs from the intracellular form and may prove to be a target for chemotherapeutic drugs.

Mammalian cells contain four distinct members of the hsp90 molecular chaperone family. The cytosolic heat shock protein hsp90 has two isoforms, hsp90a and hsp90b, which are 76% identical and are thought to be the consequence of a gene duplication event. A third family member, the 94kDa glucose-regulated protein (GRP94), is localized primarily to the endoplasmic reticulum and shows 50% homology with hsp90. Lastly, the fourth family member, TRAP-1, is primarily located in the mitochondria of mammalian cells. While hsp90 has been linked to cancer development, normal cells also require it.

Investigators at Tufts University (Boston, MA, USA) reported in the June 2004 issue of Nature Cell Biology that they had found that hps90a was expressed extracellularly, where it interacted with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90a was found to decrease both MMP2 activity and invasiveness. This role for extracellular hsp90a in MMP2 activation leads to the possibility that anti-hsp90 drugs unable to penetrate the cell membrane might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.

"This work highlights the relevance of validating function at the protein level. Genetic approaches would have missed the discovery of the novel mechanism of hsp90 action,” said senior author Dr. Daniel Jay, professor of medicine at Tufts University. "These results indicate a role for a functional proteomic approach in addition to genetic screens and suggest anti-hsp90 antibodies may be potential options for cancer treatment.”



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