Biomolecules & Therapeutics

  • 제32권1호
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  • Pages.115-122
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  • 2024
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Contribution of HSP90 Cleavage to the Cytotoxic Effect of Suberoylanilide Hydroxamic Acid In Vivo and the Involvement of TXNIP in HSP90 Cleavage

  • Sangkyu Park (Biotechnology Research Institute, Chungbuk National University) ;
  • Dongbum Kim (Institute of Medical Science, College of Medicine, Hallym University) ;
  • Haiyoung Jung (Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • In Pyo Choi (Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Hyung-Joo Kwon (Institute of Medical Science, College of Medicine, Hallym University) ;
  • Younghee Lee (Biotechnology Research Institute, Chungbuk National University)
  • 투고 : 2023.05.30
  • 심사 : 2023.07.21
  • 발행 : 2024.01.01
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초록

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

키워드

과제정보

This research was supported by grants from the National Research Foundation (2018R1A2B6002504, NRF2021R1A2C1006767) funded by the Ministry of Science and ICT in the Republic of Korea.

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