Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, Yunnan 650201, P.R. China.
Mol Med Rep. 2022 Feb;25(2). doi: 10.3892/mmr.2022.12588. Epub 2022 Jan 11.
Triple‑negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and it often becomes resistant to paclitaxel (PTX) therapy. Autophagy plays an important cytoprotective role in PTX‑induced tumor cell death, and targeting autophagy has been promising for improving the efficacy of tumor chemotherapy in recent years. The aim of the present study was to clarify the mechanism of PTX inducing autophagy in TNBC cells to provide a potential clinical chemotherapy strategy of PTX for TNBC. The present study reported that PTX induced both apoptosis and autophagy in MDA‑MB‑231 cells and that inhibition of autophagy promoted apoptotic cell death. Furthermore, it was found that forkhead box transcription factor O1 (FOXO1) enhanced PTX‑induced autophagy through a transcriptional activation pattern in MDA‑MB‑231 cells, which was associated with the downstream target genes autophagy related 5, class III phosphoinositide 3‑kinase vacuolar protein sorting 34, autophagy related 4B cysteine peptidase, beclin 1 and microtubule associated protein 1 light chain 3β. Knocking down FOXO1 attenuated the survival of MDA‑MB‑231 cells in response to PTX treatment. These findings may be beneficial for improving the treatment efficacy of PTX and to develop autophagic targeted therapy for TNBC.
三阴性乳腺癌(TNBC)是乳腺癌中侵袭性最强的亚型,它通常对紫杉醇(PTX)治疗产生耐药性。自噬在 PTX 诱导的肿瘤细胞死亡中起着重要的细胞保护作用,近年来靶向自噬已成为提高肿瘤化疗疗效的有希望的方法。本研究旨在阐明 PTX 诱导 TNBC 细胞自噬的机制,为 TNBC 的 PTX 临床化疗策略提供潜在依据。本研究报道,PTX 诱导 MDA-MB-231 细胞发生凋亡和自噬,并且自噬抑制促进了凋亡细胞死亡。此外,研究发现叉头框转录因子 O1(FOXO1)通过 MDA-MB-231 细胞中的转录激活模式增强了 PTX 诱导的自噬,这与下游靶基因自噬相关蛋白 5、III 类磷酸肌醇 3-激酶液泡分选蛋白 34、自噬相关蛋白 4B 半胱氨酸肽酶、beclin 1 和微管相关蛋白 1 轻链 3β有关。敲低 FOXO1 可减弱 MDA-MB-231 细胞对 PTX 治疗的存活能力。这些发现可能有助于提高 PTX 的治疗效果,并为 TNBC 开发自噬靶向治疗。