2. Academic Validation
  3. Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer

Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer

  • Drug Resist Updat. 2025 Jul:81:101226. doi: 10.1016/j.drup.2025.101226.
Muhammad Zubair Saleem 1,  Ruyi Huang 1,  Yingying Huang 2,  Xin Guo 1,  Yang Liu 1,  Miao Gao 2,  Yinjuan Fan 1,  Zhe-Sheng Chen 3,  Zun-Fu Ke 4,  Shengnan Ye 5,  Jianhua Xu 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China.
  • 2 The First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
  • 4 Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: kezunfu@mail.sysu.edu.cn.
  • 5 The First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China. Electronic address: yeshengnan63@fjmu.edu.cn.
  • 6 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China. Electronic address: xjh@fjmu.edu.cn.
PMID: 40086176 DOI: 10.1016/j.drup.2025.101226
Abstract

Aims: TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 Inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast Cancer cells by targeting TRAP1.

Methods: Breast Cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model.

Results: In hypoxia and glucose deprivation, breast Cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent Cancer cells by inducing mitochondrial Apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo Anticancer efficacy which was particularly related to OXPHOS inhibition.

Conclusions: C210 eliminates DOX-resistant quiescent breast Cancer cells by targeting TRAP1-dependent bioenergetics.

Keywords

Apoptosis; Drug resistance; HSP90; Oxidative phosphorylation; Quiescence; TRAP1.

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