Virtual prototyping study shows increased ATPase activity of Hsp90 to be the key determinant of cancer phenotype |
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Authors: | Shireen Vali Rani Pallavi Shweta Kapoor Utpal Tatu |
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Institution: | (1) Cellworks Group Inc., 13962 Pierce Road, Saratoga, CA 95070, USA;(2) Cellworks Research India Pvt. Ltd, #303 Block A, 3rd Floor, 60 Feet Road, AECS Layout, Marathahalli Post, Bangalore, Karnataka, 560037, India;(3) Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, 560012, India; |
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Abstract: | Hsp90 is an ATP-dependent molecular chaperone that regulates key signaling proteins and thereby impacts cell growth and development.
Chaperone cycle of Hsp90 is regulated by ATP binding and hydrolysis through its intrinsic ATPase activities, which is in turn
modulated by interaction with its co-chaperones. Hsp90 ATPase activity varies in different organisms and is known to be increased
in tumor cells. In this study we have quantitatively analyzed the impact of increasing Hsp90 ATPase activity on the activities
of its clients through a virtual prototyping technology, which comprises a dynamic model of Hsp90 interaction with clients
involved in proliferation pathways. Our studies highlight the importance of increased ATPase activity of Hsp90 in cancer cells
as the key modulator for increased proliferation and survival. A tenfold increase in ATPase activity of Hsp90 often seen in
cancer cells increases the levels of active client proteins such as Akt-1, Raf-1 and Cyclin D1 amongst others to about 12-,
8- and 186-folds respectively. Additionally we studied the effect of a competitive inhibitor of Hsp90 activity on the reduction
in the client protein levels. Virtual prototyping experiments corroborate with findings that the drug has almost 10- to 100-fold
higher affinity as indicated by a lower IC50 value (30–100 nM) in tumor cells with higher ATPase activity. The results also indicate a 15- to 25-fold higher efficacy
of the inhibitor in reducing client levels in tumor cells. This analysis provides mechanistic insights into the links between
increased Hsp90 ATPase activity, tumor phenotype and the hypersensitivity of tumor Hsp90 to inhibition by ATP analogs. |
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Keywords: | Anti-cancer drugs Heat shock protein Quantitative analysis Virtual prototyping Hsp90 ATPase activity |
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