Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/beta-catenin signaling pathway in taxol-resistant human lung adenocarcinoma
Document Type
Article
Publication Date
2-1-2021
Abstract
Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance. Methods: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot. Expression of 0-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3 alpha/0 was evaluated by western blot and IHC. Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxolresistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelialmesenchymal transition (EMT) through repression of the p70S6K/GSK3/0-catenin signaling pathway. Conclusions: Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/0-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.
Keywords
Lung adenocarcinoma, Triptolide, Chemoresistance, Epithelial-mesenchymal transition (EMT), Wnt
Divisions
fac_med
Funders
National Natural Science Foundation of China (NSFC)[81874396],Major Program of Shandong Province Natural Science Foundation[ZR2018ZC0232],Jinan Clinical Medicine Research Program for Thoracic Cancer[201912007],Special Construction Project Fund for Taishan Mountain Scholars of Shandong Province
Publication Title
Translational Lung Cancer Research
Volume
10
Issue
2
Publisher
Ame Publ Co
Publisher Location
FLAT-RM C 16F, KINGS WING PLAZA 1, NO 3 KWAN ST, SHATIN, HONG KONG 00000, PEOPLES R CHINA