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

Tian Y 1 , Li P 2 , Xiao Z 1 , Zhou J 1 , Xue X 3 , Jiang N 1 Show all authors , Peng C 1 , Wu L 4 , Tian H 5 , Popper H 6 , Poh ME 7 , Marcucci F 8 , Zhang C 1 , Zhao X 1

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 Department of Thoracic Surgery, Cheeloo Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
  • 6 Institute of Pathology, Medical University of Graz, Graz, Austria
  • 7 Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 8 Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, Milan, Italy
Transl Lung Cancer Res, 2021 Feb;10(2):1007-1019.
PMID: 33718039 DOI: 10.21037/tlcr-21-145

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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