• Am. J. Med. Sci. · Aug 2024

    FOXO4 suppresses cisplatin resistance of Triple-Negative Breast Cancer by inhibiting autophagy.

    • Yating Zhu, Chenguang Zhang, Qiuyu Yin, Wenting Xu, Yulou Luo, and Jianghua Ou.
    • Department of Pharmacy, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China.
    • Am. J. Med. Sci. 2024 Aug 21.

    BackgroundResistance to chemotherapy containing cisplatin (DDP) is a main challenge in the treatment of triple-negative breast cancer (TNBC). Forkhead box O4 (FOXO4) is frequently downregulated in DDP-resistant cells. However, it is unclear whether FOXO4 down-regulation is related to DDP resistance. Here, we investigated the relationship between FOXO4 and DDP resistance in TNBC.MethodsWe established the DDP-resistant cell lines MDA-MB-231/DDP and BT-549/DDP through in vitro selection. CCK-8 and colony formation assays analyzed cell growth. The resistance index was calculated. Cell autophagy was evaluated. Western blotting and qRT-PCR measured protein and gene expression. The binding between FOXO4 and TGF-β1 was determined by the dual-luciferase reporter assay.ResultsFOXO4 expression was significantly lower in MDA-MB-231/DDP and BT-549/DDP cells. FOXO4 overexpression increased the sensitivity of TNBC cells to DDP. The PI3K class Ⅲ and Beclin-1 levels and LC3-II/LC3-I ratio elevated significantly in DDP-resistant cells. Moreover, the autophagic flux was enhanced in DDP-resistant cells. 3-MA enhanced the sensitivity of TNBC cells to DDP by inhibiting autophagy. Overexpression of FOXO4, treatment with 3-MA, and their combination significantly reduced the drug resistance index. FOXO4 directly targeted TGF-β1. Additionally, TGF-β1 knockdown inhibited autophagy and restored the sensitivity of DDP-resistant cells to DDP. Mechanistically, FOXO4 affected TNBC resistance to DDP by regulating autophagy and TGF-β1.ConclusionFOXO4 overexpression, in combination with autophagy inhibitors, can significantly improve the sensitivity of TNBC-resistant cells to DDP. These findings reveal the role and mechanism of FOXO4 in DDP sensitivity and may provide evidence for the development of TNBC therapies.Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

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