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Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo

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Title Oxidative inhibition of Hsp90 disrupts the super-chaperone
complex and attenuates pancreatic adenocarcinoma in vitro
and in vivo
 
Creator Sarkar, Sayantani
Dutta, Devawati
Samanta, Suman Kumar
Bhattacharya, Kaushik
Pal, Bikas C
Li, Jinping
Datta, Kaustubh
Mandal, Chhabinath
Mandal, Chitra
 
Subject Cancer Biology and Inflammatory Disorder Division
 
Description Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress-mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid,mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa-2. N-acetyl-L-cysteine prevented mahanine-induced ROS
accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90-Cdc37 complex in MIAPaCa-2 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions
with Hsp90. However, no disruption of the Hsp90-Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced in vitro migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine-induced ROS-mediated destabilization of Hsp90 chaperone activity resulting in Hsp90-Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer



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Publisher John Wiley & Sons
 
Date 2013
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1948/1/INTERNATIONAL_JOURNAL_OF_CANCER__Volume_132(_3)__695%2D706;2013[117].pdf
Sarkar, Sayantani and Dutta, Devawati and Samanta, Suman Kumar and Bhattacharya, Kaushik and Pal, Bikas C and Li, Jinping and Datta, Kaustubh and Mandal, Chhabinath and Mandal, Chitra (2013) Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo. International Journal of Cancer, 132 (3). pp. 695-706. ISSN 0020-7136
 
Relation http://dx.doi.org/10.1002/ijc.27687
http://www.eprints.iicb.res.in/1948/