2. Academic Validation
  3. HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling

HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling

  • Int J Biol Sci. 2024 Sep 23;20(13):5162-5190. doi: 10.7150/ijbs.100015.
Yiming Zhang 1,  Ruilin Pan 1,  Kun Li 1 2,  Lek Hang Cheang 3,  Jing Zhao 4,  Zhangfeng Zhong 4,  Shaoping Li 4,  Jinghao Wang 5 6,  Xiaofang Zhang 5 7,  Yanmei Cheng 8,  Xiaofei Zheng 1,  Rongrong He 2,  Huajun Wang 1
Affiliations

Affiliations

  • 1 Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, Guangzhou, China.
  • 2 State Key Laboratory of Bioactive Molecules and Drug Ability Assessment, Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of the Chinese Ministry of Education, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, China.
  • 3 Department of Orthopedic Surgery, Centro Hospitalar Conde de Sao Januario, Macau, China.
  • 4 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, China.
  • 5 Department of Pharmacy, the First Affiliated Hospital, State Key Laboratory of Frigid Zone Cardiovascular Diseases, Jinan University, Guangzhou, China.
  • 6 Department of Orthopedics, NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 7 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, Heilongjiang, China.
  • 8 Department of Cardiothoracic Surgery ICU, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
PMID: 39430254 DOI: 10.7150/ijbs.100015
Abstract

Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and Apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating Akt/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the Akt/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.

Keywords

ATP5A1; HSPD1; multiomics analysis; osteosarcoma; oxidative phosphorylation; ubiquitination.

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