PMID- 37481142 OWN - NLM STAT- MEDLINE DCOM- 20230906 LR - 20230918 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 215 DP - 2023 Sep TI - Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells. PG - 115690 LID - S0006-2952(23)00281-2 [pii] LID - 10.1016/j.bcp.2023.115690 [doi] AB - Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved. FAU - Cui, Jinling AU - Cui J AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Zhao, Shuang AU - Zhao S AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Chen, Hui AU - Chen H AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Fu, Yuhan AU - Fu Y AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Han, Kai AU - Han K AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Yin, Shutao AU - Yin S AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. Electronic address: yinshutao@cau.edu.cn. FAU - Zhao, Chong AU - Zhao C AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. FAU - Fan, Lihong AU - Fan L AD - College of Veterinary Medicine, China Agricultural University, No.2 Yunamingyuan West Road, Haidian District, Beijing 100193, China. Electronic address: flh@cau.edu.cn. FAU - Hu, Hongbo AU - Hu H AD - College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, No.17 Qinghua East Road, Haidian District, Beijing 100083, China. Electronic address: hongbo@cau.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230720 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - S65743JHBS (Gefitinib) RN - 9900C6V162 (methylselenic acid) RN - 7006-34-0 (Asparagine) RN - EC 2.7.10.1 (ErbB Receptors) RN - 0 (Quinazolines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Antineoplastic Agents) SB - IM MH - Humans MH - *Carcinoma, Non-Small-Cell Lung/genetics MH - Gefitinib/pharmacology/therapeutic use MH - Asparagine MH - *Lung Neoplasms/pathology MH - ErbB Receptors/metabolism MH - Quinazolines/pharmacology MH - Drug Resistance, Neoplasm MH - Cell Line, Tumor MH - Protein Kinase Inhibitors/pharmacology MH - Cell Proliferation MH - *Antineoplastic Agents/pharmacology/therapeutic use OTO - NOTNLM OT - Asparagine OT - Gefitinib resistance OT - MET OT - Methylseleninic acid OT - NSCLC COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/07/23 01:11 MHDA- 2023/09/06 06:42 CRDT- 2023/07/22 19:25 PHST- 2023/04/16 00:00 [received] PHST- 2023/07/08 00:00 [revised] PHST- 2023/07/11 00:00 [accepted] PHST- 2023/09/06 06:42 [medline] PHST- 2023/07/23 01:11 [pubmed] PHST- 2023/07/22 19:25 [entrez] AID - S0006-2952(23)00281-2 [pii] AID - 10.1016/j.bcp.2023.115690 [doi] PST - ppublish SO - Biochem Pharmacol. 2023 Sep;215:115690. doi: 10.1016/j.bcp.2023.115690. Epub 2023 Jul 20.