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

Sep 22, 2026

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Drug resistance is a central cause of chemotherapy failure, promoting stem-like cancer traits, metastasis, and relapse. Luteolin, a natural flavonoid with anti-tumor activity, was investigated for its protective effects in paclitaxel (PTX)-resistant esophageal squamous cell carcinoma. Cell and molecular assays evaluated proliferation, clonogenicity, cell cycle arrest, apoptosis, migration, invasion, EMT, and stemness. High-throughput sequencing and PI3K/Akt pathway verification, supported by molecular docking, indicated luteolin suppresses tumor resistance by downregulating the FAK/PI3K/AKT pathway and shows limited in vivo toxicity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Experimental approaches

Mechanistic pathway analysis

In vivo assessment

Introduction

Esophageal cancer background

Chemotherapy resistance and rationale

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 54: 77, 2024 Luteolin enhances drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in paclitaxel‑resistant esophageal squamous cell carcinoma ZHENZHEN YANG 1,2 , HONGTAO LIU3 , YINSEN SONG 1 , NA GAO 1,2 , PAN GAO 1,2 , YIRAN HUI2,4 , YUEHENG LI2 and TIANLI FAN2 1The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan 450003, P.R. China; 2School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China; 3School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China; 4University of Chinese Academy of Sciences Shenzhen Hospital, Shenzhen, Guangdong 518107, P.R. China Received March 28, 2024; Accepted June 12, 2024 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 eluci‑ dated. 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 inva‑ sion 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 prolif‑ eration, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX‑resistant esophageal squamous cell carcinoma Correspondence to: Professor Tianli Fan, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450001, P.R. China E‑mail: [fantianli@zzu.edu.cn](fantianli@zzu.edu.cn) Key words: luteolin, esophageal squamous cell carcinoma, drug chemosensitivity, molecular docking, focal adhesion kinase/PI3K/AKT pathway (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. Introduction Esophageal cancer (EC) is one of the most common and lethal malignant tumors of the digestive tract (1) . It is characterized by aggressive metastasis, which leads to a poor prognosis and low 5‑year survival rates (2) . Esophageal squamous cell carcinoma (ESCC) is a common histopathological subtype worldwide and is estimated to account for 90% of EC cases in China (3‑4). According to the specific stage of the disease, treatment methods primarily include surgery, chemotherapy and radiotherapy. However, despite thorough investigations by the research community, the prognosis of the disease has not improved markedly in the past 20 year

FAQs

What problem does the study address in esophageal squamous cell carcinoma?

It targets drug resistance that undermines tumor chemotherapy effectiveness, contributing to metastasis, relapse, and poor prognosis in esophageal squamous cell carcinoma.

How does luteolin affect PTX-resistant cancer cells according to the abstract?

Luteolin inhibits proliferation, induces cell cycle arrest and apoptosis, and hinders migration and invasion in PTX-resistant esophageal squamous cell carcinoma cells.

Which molecular signaling pathway is implicated in the study’s mechanism?

The study proposes that luteolin enhances drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway, potentially through binding to active sites involving FAK, Src, and AKT.

Sep 22, 2026

Upload by Oliver