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PTEN status determines therapeutic vulnerability to celastrol in cholangiocarcinoma.
Pan, Yu-Fei; Zhong, Lin; Wang, Min; Jiang, Tian-Yi; Lin, Yun-Kai; Chen, Yi-Bin; Li, Xin; Hu, He-Ping; Zhou, Hua-Bang; Yan, Hong-Zhu; Dong, Li-Wei.
Afiliação
  • Pan YF; National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education. 225 Changhai Road, Shanghai 200438, China.
  • Zhong L; Department of Pathology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (TCM), 358 Datong Road, Shanghai, 200137, China.
  • Wang M; Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 700 Moyu Road, Shanghai, 201805, China.
  • Jiang TY; National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education. 225 Changhai Road, Shanghai 200438, China.
  • Lin YK; National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China.
  • Chen YB; National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China.
  • Li X; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education. 225 Changhai Road, Shanghai 200438, China.
  • Hu HP; Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, 700 Moyu Road, Shanghai, 201805, China.
  • Zhou HB; Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, 700 Moyu Road, Shanghai, 201805, China. Electronic address: zhouhb513@126.com.
  • Yan HZ; Department of Pathology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (TCM), 358 Datong Road, Shanghai, 200137, China. Electronic address: yanhongzhu2012@163.com.
  • Dong LW; National Center for Liver Cancer, Naval Medical University, 366 Qianju Road, Shanghai, 201805, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education. 225 Changhai Road, Shanghai 200438, China. Electronic address: donliwei@126.com.
Phytomedicine ; 131: 155790, 2024 Aug.
Article em En | MEDLINE | ID: mdl-38851099
ABSTRACT

BACKGROUND:

A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear.

PURPOSE:

We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors.

METHODS:

Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured.

RESULTS:

Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol PTENhigh tumor cells were resistant to celastrol, while PTENlow cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTENlow CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTENhigh CCA cells. Disrupting the autophagic pathway in PTENhigh CCA cells enhanced the cytotoxic effect of celastrol.

CONCLUSION:

PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTENhigh CCA.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Triterpenos / Neoplasias dos Ductos Biliares / Colangiocarcinoma / PTEN Fosfo-Hidrolase / Triterpenos Pentacíclicos Limite: Humans Idioma: En Revista: Phytomedicine Assunto da revista: TERAPIAS COMPLEMENTARES Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Triterpenos / Neoplasias dos Ductos Biliares / Colangiocarcinoma / PTEN Fosfo-Hidrolase / Triterpenos Pentacíclicos Limite: Humans Idioma: En Revista: Phytomedicine Assunto da revista: TERAPIAS COMPLEMENTARES Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China