Luteolin enhances drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in paclitaxel‑resistant esophageal squamous cell carcinoma.

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
International journal of molecular medicine Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI:10.3892/ijmm.2024.5401
Zhenzhen Yang, Hongtao Liu, Yinsen Song, Na Gao, Pan Gao, Yiran Hui, Yueheng Li, Tianli Fan
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引用次数: 0

Abstract

Drug resistance is a key factor underlying the failure of tumor chemotherapy. It enhances the stem‑like cell properties of cancer cells, tumor metastasis and relapse. Luteolin is a natural flavonoid with strong anti‑tumor effects. However, the mechanism(s) by which luteolin protects against paclitaxel (PTX)‑resistant cancer cell remains to be elucidated. The inhibitory effect of luteolin on the proliferation of EC1/PTX and EC1 cells was detected by cell counting kit‑8 assay. Colony formation and flow cytometry assays were used to assess clonogenic capacity, cell cycle and apoptosis. Wound healing and Transwell invasion tests were used to investigate the effects of luteolin on the migration and invasion of EC1/PTX cells. Western blotting was used to detect the protein levels of EMT‑related proteins and stem cell markers after sphere formation. Parental cells and drug‑resistant cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. ELISA and western blotting were used to verify the screened PI3K/Akt signaling pathway, key proteins of which were explored by molecular docking. Hematoxylin and eosin staining and TUNEL staining were used to observe tumor xenografts on morphology and apoptosis in nude mice. The present study found that luteolin inhibited tumor resistance (inhibited proliferation, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX‑resistant esophageal squamous cell carcinoma (ESCC) cells. In addition, luteolin enhanced drug sensitivity and promoted the apoptosis of drug‑resistant ESCC cells in combination with PTX. Mechanistically, luteolin may inhibit the PI3K/AKT signaling pathway by binding to the active sites of focal adhesion kinase (FAK), Src and AKT. Notably, luteolin lowered the tumorigenic potential of PTX‑resistant ESCC cells but did not show significant toxicity in vivo. Luteolin enhanced drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in PTX‑resistant ESCC and could be a promising agent for the treatment of PTX‑resistant ESCC cancers.

木犀草素通过下调紫杉醇耐药食管鳞癌的FAK/PI3K/AKT通路增强药物化疗敏感性
耐药性是肿瘤化疗失败的一个关键因素。它能增强癌细胞的干样细胞特性,促进肿瘤转移和复发。叶黄素是一种天然类黄酮,具有很强的抗肿瘤作用。然而,叶黄素保护紫杉醇(PTX)耐药癌细胞的机制仍有待阐明。叶黄素对 EC1/PTX 和 EC1 细胞增殖的抑制作用是通过细胞计数试剂盒-8 检测的。集落形成和流式细胞术检测用于评估细胞的克隆生成能力、细胞周期和细胞凋亡。伤口愈合和 Transwell 侵袭试验用于研究木犀草素对 EC1/PTX 细胞迁移和侵袭的影响。用 Western 印迹法检测球形成后 EMT 相关蛋白和干细胞标记物的蛋白水平。通过高通量测序筛选亲代细胞和耐药细胞,检测RNA和不同基因的差异表达。用ELISA和Western印迹法验证筛选出的PI3K/Akt信号通路,并通过分子对接法探索其中的关键蛋白。血红素和伊红染色以及TUNEL染色用于观察裸鼠肿瘤异种移植的形态和凋亡情况。本研究发现,在体外实验中,叶黄素可抑制对PTX耐药的食管鳞状细胞癌(ESCC)细胞的肿瘤耐药性(抑制增殖、诱导细胞周期停滞和凋亡、阻碍迁移侵袭、EMT和干细胞球化)。此外,叶黄素还能增强耐药 ESCC 细胞对 PTX 的药物敏感性并促进其凋亡。从机理上讲,叶黄素可通过与焦点粘附激酶(FAK)、Src和AKT的活性位点结合来抑制PI3K/AKT信号通路。值得注意的是,叶黄素降低了耐 PTX ESCC 细胞的致瘤潜能,但在体内并未显示出明显的毒性。叶黄素通过下调PTX耐药ESCC细胞的FAK/PI3K/AKT通路增强了药物的化疗敏感性,可能是治疗PTX耐药ESCC癌症的一种有前途的药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International journal of molecular medicine
International journal of molecular medicine 医学-医学:研究与实验
CiteScore
12.30
自引率
0.00%
发文量
124
审稿时长
3 months
期刊介绍: The main aim of Spandidos Publications is to facilitate scientific communication in a clear, concise and objective manner, while striving to provide prompt publication of original works of high quality. The journals largely concentrate on molecular and experimental medicine, oncology, clinical and experimental cancer treatment and biomedical research. All journals published by Spandidos Publications Ltd. maintain the highest standards of quality, and the members of their Editorial Boards are world-renowned scientists.
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