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Inhibition of HSP90 reverses STAT3-mediated muscle wasting in cancer cachexia mice.
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  • Mengyuan Niu,
  • Shiyu Song,
  • Zhonglan Su,
  • Lulu Wei,
  • Li Li,
  • Wenyuan Pu,
  • Chen Zhao,
  • Yibing Ding,
  • Jinglin Wang,
  • Wangsen Cao,
  • Qian Gao,
  • hongwei Wang
Mengyuan Niu
Nanjing University
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Shiyu Song
Nanjing University
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Zhonglan Su
Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital
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Lulu Wei
Nanjing University
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Li Li
Nanjing University
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Wenyuan Pu
Nanjing University
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Chen Zhao
Nanjing University
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Yibing Ding
Nanjing University
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Jinglin Wang
Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
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Wangsen Cao
Nanjing University
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Qian Gao
Nanjing University
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hongwei Wang
Nanjing University
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Abstract

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic animal models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms remain incompletely understood. Here, we show that an enhanced interaction between activated STAT3 and HSP90, which were observed in the skeletal muscle of cancer cachexia patients, is a crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors 17DMAG and PU-H71 alleviated the muscle wasting in C26 tumor-bearing cachectic mice or the myotube atrophy of C2C12 cells induced by C26 conditional medium. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation transactivated FOXO1 by binding directly to its promoter and triggered the muscle wasting in a FOXO1-dependent manner; Our results demonstrate that the HSP90/STAT3/FOXO1 axis plays a critical role in the cachectic muscle wasting, which might serve as potential therapeutic target for the treatment of cancer cachexia.

Peer review status:UNDER REVIEW

15 Mar 2021Submitted to British Journal of Pharmacology
17 Mar 2021Submission Checks Completed
17 Mar 2021Assigned to Editor
06 Apr 2021Review(s) Completed, Editorial Evaluation Pending
10 Apr 2021Editorial Decision: Revise Minor
13 Apr 20211st Revision Received
14 Apr 2021Assigned to Editor
14 Apr 2021Submission Checks Completed
26 Apr 2021Reviewer(s) Assigned
15 May 2021Review(s) Completed, Editorial Evaluation Pending
23 May 2021Editorial Decision: Revise Minor
10 Jun 20212nd Revision Received
17 Jun 2021Submission Checks Completed
17 Jun 2021Assigned to Editor
21 Jun 2021Reviewer(s) Assigned
22 Jun 2021Review(s) Completed, Editorial Evaluation Pending