Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway

Sep 24, 2026

Breast cancer chemoresistance presents a major barrier to improving patient outcomes, with doxorubicin (Dox) resistance being especially challenging. This study investigates how the FABP signaling axis regulates Dox resistance by linking FABP5 to PPARγ and CaMKII activation. Dox-resistant MCF-7/ADR cells and corresponding patient tissues were evaluated using CCK-8, Western blot, confocal microscopy, calcium assays, immunohistochemistry, and molecular docking. FABP5 inhibition reduced intracellular calcium, PPARγ and autophagy and increased Dox sensitivity, identifying FABP5 as a therapeutically targetable biomarker.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

1 Introduction

TYPE Original Research PUBLISHED 19 July 2023 DOI 10.3389/fphar.2023.1150861 OPEN ACCESS EDITED BY Karina Felipe, Federal University of Paraná, Brazil REVIEWED BY Rozangela Curi Pedrosa, Federal University of Santa Catarina, Brazil Subhayan Das, Indian Institute of Technology Kharagpur, India Eduardo Parisotto, Federal University of Mato Grosso do Sul, Brazil *CORRESPONDENCE Su-Wen Su, [suswmk@hebmu.edu.cn](suswmk@hebmu.edu.cn)[ ](suswmk@hebmu.edu.cn)Yun-Jiang Liu, [lyj818326@outlook.com](lyj818326@outlook.com) RECEIVED 25 January 2023 ACCEPTED 06 July 2023 PUBLISHED 19 July 2023 CITATION Chen N-N, Ma X-D, Miao Z, Zhang X-M, Han B-Y, Almaamari AA, Huang J-M, Chen X-Y, Liu Y-J and Su S-W (2023), Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/ PPARγ and CaMKII signaling pathway. Front. Pharmacol. 14:1150861 . doi: 10.3389/fphar.2023.1150861 COPYRIGHT © 2023 Chen, Ma, Miao, Zhang, Han, Almaamari, Huang, Chen, Liu and Su. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Doxorubicin resistance in breast cancer is mediated via the activation of FABP5/PPARγ and CaMKII signaling pathway Nan-Nan Chen 1, Xin-Di Ma 2, Zhuang Miao 1, Xiang-Mei Zhang 3, Bo-Ye Han 1, Ahmed Ali Almaamari 1, Jia-Min Huang 1, Xue-Yan Chen 1, Yun-Jiang Liu 2* and Su-Wen Su 1* 1The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China, 2Breast Center, Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China, 3Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China Breast cancer is the most prevalent malignancy among women. Doxorubicin (Dox) resistance was one of the major obstacles to improving the clinical outcome of breast cancer patients. The purpose of this study was to investigate the relationship between the FABP signaling pathway and Dox resistance in breast cancer. The resistance property of MCF-7/ADR cells was evaluated employing CCK-8, Western blot (WB), and confocal microscopy techniques. The glycolipid metabolic properties of MCF-7 and MCF-7/ADR cells were identiﬁed using transmission electron microscopy, PAS, and Oil Red O staining. FABP5 and CaMKII expression levels were assessed through GEO and WB approaches. The intracellular calcium level was determined by ﬂow cytometry. Clinical breast cancer patient’s tumor tissues were evaluated by immunohistochemistry to determine FABP5 and p-CaMKII protein expression. In the presence or absence of FABP5 siRNA or the FABP5-speciﬁc inhibitor SBFI-26, Dox resistance was investigated utilizing CCK-8, WB, and colony formation methods, and intracellular calcium level was examined. The binding ability of Dox was explored by molecular docking analysis. The results indicated that the MCF-7/ADR cells we employed were Dox-resistant MCF-7 cells. FABP5 expression was considerably elevated in MCF-7/ADR cells compared to parent MCF-7 cells. FABP5 and p-CaMKII expression were increased in resistant patients than in sensitive individuals. Inhibition of the protein expression of FABP5 by siRNA or inhibitor increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy. Molecular docking results showed that FABP5 binds more powerfully to Dox than the known drug resistance-associated protein P-GP. In summary, the PPARγ and CaM

FAQs

What is the main goal of this study?

To investigate the relationship between the FABP signaling pathway and doxorubicin resistance in breast cancer, focusing on FABP5-related activation of PPARγ and CaMKII.

How was Dox resistance evaluated in the experiments?

Dox resistance was assessed in MCF-7/ADR cells using CCK-8, Western blot, and colony formation methods, along with intracellular calcium measurements by flow cytometry.

What effect did FABP5 inhibition have on Dox-resistant cells?

Silencing FABP5 with siRNA or inhibiting it increased Dox sensitivity in MCF-7/ADR cells and lowered intracellular calcium, PPARγ, and autophagy.

Sep 24, 2026

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