Secreted Heat Shock Protein-90α: A More Effective and Safer Target for Anti-Cancer Drugs?

Author(s): Chieh-Fang Cheng, Jianhua Fan, Zhengwei Zhao, David T. Woodley, Wei Li

Journal Name: Current Signal Transduction Therapy

Volume 5 , Issue 2 , 2010

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Until recently, heat shock protein 90 (Hsp90) has been mostly known as an abundant intracellular chaperone with more than 100 target proteins often involved in control of cell metabolism, survival, growth and differentiation. Hsp90 has been a target for anti-cancer drugs, since it was found either overexpressed or overactive in cancer cells. For more than a decade, geldanamycin (GM)-derived inhibitors of Hsp90s ATPase have entered various clinical trials around the world. Despite of high expectations, the efficacy of these inhibitors in humans has been less than what was hoped for. While newer generations of GM inhibitors are being developed and tested in several ongoing clinical trials, recent studies have discovered a surprising need for cancer cells to constitutively secrete Hsp90α for invasion and metastasis. A main function for secreted Hsp90 is to promote cell motility via the cell surface receptor LRP1 and/or secreted MMP2. Distinct from its intracellular chaperone function that requires the N-terminal ATPase and the C-terminal dimerization, the pro-motility activity of extracellular Hsp90α resides in a highly charged peptide between the linker region and the middle domain in Hsp90α. Selective inhibition of secreted Hsp90α blocks tumor cell invasion in vitro and in vivo. More importantly, since Hsp90α secretion does not occur in normal cells under physiological conditions, drugs that selectively target the secreted Hsp90α at its pro-motility region may prove to be more effective and less toxic for treatment of cancer patients.

Keywords: HSP90, secretion, cell migration, cancer progression, anti-cancer target

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Article Details

Year: 2010
Page: [121 - 127]
Pages: 7
DOI: 10.2174/157436210791112208
Price: $65

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