PMID- 33718039 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220421 IS - 2218-6751 (Print) IS - 2226-4477 (Electronic) IS - 2218-6751 (Linking) VI - 10 IP - 2 DP - 2021 Feb TI - Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/beta-catenin signaling pathway in taxol-resistant human lung adenocarcinoma. PG - 1007-1019 LID - 10.21037/tlcr-21-145 [doi] AB - 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 beta-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-3alpha/beta 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/beta-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/beta-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma. CI - 2021 Translational Lung Cancer Research. All rights reserved. FAU - Tian, Yu AU - Tian Y AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Li, Peiwei AU - Li P AD - Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Xiao, Zhaohua AU - Xiao Z AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Zhou, Jie AU - Zhou J AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Xue, Xia AU - Xue X AD - Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Jiang, Ning AU - Jiang N AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Peng, Chuanliang AU - Peng C AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Wu, Licun AU - Wu L AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada. FAU - Tian, Hui AU - Tian H AD - Department of Thoracic Surgery, Cheeloo Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Popper, Helmut AU - Popper H AD - Institute of Pathology, Medical University of Graz, Graz, Austria. FAU - Poh, Mau-Ern AU - Poh ME AD - Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. FAU - Marcucci, Fabrizio AU - Marcucci F AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, via Trentacoste 2, Milan, Italy. FAU - Zhang, Chengke AU - Zhang C AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Zhao, Xiaogang AU - Zhao X AD - Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. AD - Key Laboratory of Thoracic Cancer, Cheeloo College of Medicine, Shandong University, Jinan, China. LA - eng PT - Journal Article PL - China TA - Transl Lung Cancer Res JT - Translational lung cancer research JID - 101646875 PMC - PMC7947389 OTO - NOTNLM OT - Lung adenocarcinoma OT - Wnt OT - chemoresistance OT - epithelial-mesenchymal transition (EMT) OT - triptolide COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-145). HP serves as an unpaid Associate Editor (Controversies on Lung Cancer: Pros and Cons) of Translational Lung Cancer Research from Jul. 2019 to Jul. 2021. The other authors have no conflicts of interest to declare. EDAT- 2021/03/16 06:00 MHDA- 2021/03/16 06:01 PMCR- 2021/02/01 CRDT- 2021/03/15 07:07 PHST- 2021/03/15 07:07 [entrez] PHST- 2021/03/16 06:00 [pubmed] PHST- 2021/03/16 06:01 [medline] PHST- 2021/02/01 00:00 [pmc-release] AID - tlcr-10-02-1007 [pii] AID - 10.21037/tlcr-21-145 [doi] PST - ppublish SO - Transl Lung Cancer Res. 2021 Feb;10(2):1007-1019. doi: 10.21037/tlcr-21-145.