Vol.45, No.3, 2021, pp.617-625, doi:10.32604/biocell.2021.012504
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ARTICLE
Thymidylate synthase confers pemetrexed resistance of non-small cell lung cancer cells by EGFR/PI3K/AKT pathway
  • DAN ZHANG1, HAIJING LIU1, ZHENNAN YI2, YUANYUAN LU3, YANYAN CHEN4, WEIQIANG SU2, HUIBING LIN2, ZHIHUI ZHANG5,*, WEI LEI6,*
1 Department of Oncology, Center People’s Hospital of Zhanjiang, Zhanjiang, 524000, China
2 Department of Respiration, Center People’s Hospital of Zhanjiang, Zhanjiang, 524000, China
3 Department of Oncology, Yijishan Hospital Affiliated to Wannan Medical College, Wuhu, 241001, China
4 Department of Oncology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
5 Department of Thoracic Surgery, Center People’s Hospital of Zhanjiang, Zhanjiang, 524000, China
6 Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
* Address correspondence to: Zhihui Zhang, ; Wei Lei,
Received 02 July 2020; Accepted 28 September 2020; Issue published 03 March 2021
Abstract
Chemotherapy drug resistance is the main cause leading to the relapse and metastasis of non-small cell lung cancer (NSCLC) patients. Our study aimed to investigate the mechanism of pemetrexed resistance in NSCLC. Firstly, the pemetrexed (PEM)-resistant PC-9 and A549 lung adenocarcinoma cell lines (PC-9/PEM and A549/PEM) were established. The expression of thymidylate synthase (TS) in PC-9/PEM, A549/PEM, A549, and PC-9 cells were analyzed by qRT-PCR and western blot. Then, cell viability, colony formation, migration, and invasion were performed on PEM-resistant cells transfected with TS siRNA. The role of EGFR in PEM resistance of PEM-resistant cells was investigated using EGFR siRNA. The effects of gefitinib and EGFR siRNA on EGFR/PI3K/AKT pathway and downstream signaling Cyclin D1 and E2F1 in PEM-resistant cells were analyzed. Results showed that the protein level of TS was significantly increased in A549/PEM and PC-9/PEM. TS knockdown inhibited the potency of proliferation, colony-forming potential, migration, and invasion in PEM-resistant cells. EGFR knockdown abrogated the resistance to PEM of PEM-resistant cells and suppressed the migration and invasion of PEM-resistant cells. Gefitinib treatment and EGFR knockdown respectively inhibited the EGFR/PI3K/AKT pathway and downregulated Cyclin D1 and E2F1 in PEM-resistant cells. Thus, TS might be a predictive marker for PEM resistance in NSCLC. Inhibition of the EGFR pathway abrogated the resistance to PEM and inhibited the EGFR/PI3K/AKT and downstream signaling of PEMresistant NSCLC cell lines.
Keywords
NSCLC cell lines, Pemetrexed, EGFR, PI3K, AKT, Thymidylate synthase
Cite This Article
ZHANG, D., LIU, H., YI, Z., LU, Y., CHEN, Y. et al. (2021). Thymidylate synthase confers pemetrexed resistance of non-small cell lung cancer cells by EGFR/PI3K/AKT pathway. BIOCELL, 45(3), 617–625.
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