作者列表：Zhenzhen Yang, Hongtao Liu, Yinsen Song, Na Gao, Pan Gao, Yiran Hui, Yueheng Li, Tianli Fan

期刊：INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

影响因子：5.7

DOI:10.3892/ijmm.2024.5401

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.