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

Muhammad Zubair Saleem1, Ruyi Huang1, Yingying Huang2

  • 1School of Pharmacy, Fujian Medical University, Fuzhou 350122, China; Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|March 14, 2025
PubMed
Abstract

Insights

A novel inhibitor, C210, targets TRAP1 to eliminate drug-resistant quiescent breast cancer cells. This approach disrupts cellular bioenergetics, specifically targeting oxidative phosphorylation (OXPHOS) for cancer cell elimination.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Heat shock protein 90 (HSP90) and its homolog TRAP1 are implicated in cancer cell metabolism and drug resistance.
  • Quiescent breast cancer cells exhibit metabolic reprogramming and resistance to conventional chemotherapy, such as doxorubicin (DOX).

Purpose of the Study:

  • To investigate the efficacy of a novel HSP90 inhibitor, C210, in overcoming DOX resistance in quiescent breast cancer cells.
  • To elucidate the mechanism by which C210 targets TRAP1 and affects cellular metabolism and survival.

Main Methods:

  • Induction of breast cancer cell quiescence via hypoxia and glucose deprivation.
  • Assessment of cellular metabolism using Western blotting, ECAR, OCR, mitochondrial complex activity assays, and proteomic analysis.
  • Investigation of C210's targets and functions using SPR and immunoprecipitation, with in vivo efficacy evaluated in a mouse tumor model.

Main Results:

  • Quiescent cells under hypoxia and low glucose displayed elevated TRAP1, enhanced oxidative phosphorylation (OXPHOS), and DOX resistance, but were sensitive to C210.
  • C210 disrupted TRAP1 interactions, leading to proteasomal degradation of OXPHOS proteins, reduced mitochondrial respiration, and apoptosis in quiescent cells.
  • C210 also targeted glycolytic, amino acid, and beta-oxidation pathways, demonstrating significant in vivo anticancer activity linked to OXPHOS inhibition.

Conclusions:

  • C210 effectively eliminates doxorubicin-resistant quiescent breast cancer cells.
  • The mechanism involves targeting TRAP1-dependent bioenergetics and inhibiting OXPHOS.
Keywords:
ApoptosisDrug resistanceHSP90Oxidative phosphorylationQuiescenceTRAP1

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