2. Academic Validation
  3. Obesity-driven oleoylcarnitine accumulation in tumor microenvironment promotes breast cancer metastasis-like phenotype

Obesity-driven oleoylcarnitine accumulation in tumor microenvironment promotes breast cancer metastasis-like phenotype

  • Acta Pharm Sin B. 2025 Apr;15(4):1974-1990. doi: 10.1016/j.apsb.2025.02.026.
Chao Chen 1,  Hongxia Zhang 1,  Lingling Qi 1,  Haoqi Lei 1,  Xuefei Feng 1,  Yingjie Chen 1,  Yuanyuan Cheng 1,  Defeng Pang 1,  Jufeng Wan 1,  Haiying Xu 1,  Shifeng Cao 1,  Baofeng Yang 1 2,  Yan Zhang 1 3,  Xin Zhao 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 2 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin 150081, China.
  • 3 Institute of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
PMID: 40486851 DOI: 10.1016/j.apsb.2025.02.026
Abstract

Obesity is a significant risk factor for Cancer and is associated with breast Cancer metastasis. Nevertheless, the mechanism by which alterations in systemic metabolism affect tumor microenvironment (TME) and consequently influence tumor metastasis remains inadequately understood. Herein, we found that perturbations in circulating metabolites induced by obesity promote metastasis-like phenotypes in breast Cancer. Oleoylcarnitine (OLCarn) concentrations were elevated in the serum of obese mice and humans. Administration of exogenous OLCarn induces metastasis-like characteristics in breast Cancer cells. Mechanistically, OLCarn directly interacts with the Arg176 site of Adenylate Cyclase 10 (ADCY10), leading to the activation of ADCY10 and enhancement of cAMP production. Mutations at Arg176 prevent OLCarn from binding to ADCY10, disrupting the ADCY10-mediated activation of cyclic adenosine monophosphate (cAMP) signaling pathway. This activation promotes transcription factor 4 (TCF4)-dependent Kinesin family member C1 (KIFC1) transcription, thereby driving breast Cancer metastasis. Conversely, the neutralization of both ADCY10 and KIFC1 through knockdown or pharmacological inhibition abrogates the oncogenic effects mediated by OLCarn. Hence, obesity-induced systemic environmental changes lead to the aberrant accumulation of OLCarn within the TME, making it a potential therapeutic target and biomarker for breast Cancer.

Keywords

ADCY10; Breast cancer; Epithelial–mesenchymal transition; KIFC1; Metabolite; Obesity; Oleoylcarnitine; cAMP.

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