Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/β-catenin signaling pathway in taxol-resistant human lung adenocarcinoma

Yu Tian; Peiwei Li; Zhaohua Xiao; Jie Zhou; Xia Xue; Ning Jiang; Chuanliang Peng; Licun Wu; Hui Tian; Helmut Popper; Mau-Ern Poh; Fabrizio Marcucci; Chengke Zhang; Xiaogang Zhao

doi:10.21037/tlcr-21-145

Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/β-catenin signaling pathway in taxol-resistant human lung adenocarcinoma

Transl Lung Cancer Res. 2021 Feb;10(2):1007-1019. doi: 10.21037/tlcr-21-145.

Authors

Yu Tian¹, Peiwei Li², Zhaohua Xiao¹, Jie Zhou¹, Xia Xue^{3

4}, Ning Jiang^{1

4}, Chuanliang Peng^{1

4}, Licun Wu^{4

5}, Hui Tian⁶, Helmut Popper⁷, Mau-Ern Poh⁸, Fabrizio Marcucci⁹, Chengke Zhang^{1

4}, Xiaogang Zhao^{1

4}

Affiliations

¹ Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁴ Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁵ Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada.
⁶ Department of Thoracic Surgery, Cheeloo Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁷ Institute of Pathology, Medical University of Graz, Graz, Austria.
⁸ Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁹ Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, Milan, Italy.

Abstract

Background: 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 β-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-3α/β was evaluated by western blot and IHC.

Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxol-resistant 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 epithelial-mesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-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/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

Keywords: Lung adenocarcinoma; Wnt; chemoresistance; epithelial-mesenchymal transition (EMT); triptolide.