2. Academic Validation
  3. Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells

Methylseleninic acid overcomes gefitinib resistance through asparagine-MET-TOPK signaling axis in non-small cell lung cancer cells

  • Biochem Pharmacol. 2023 Jul 20;215:115690. doi: 10.1016/j.bcp.2023.115690.
Jinling Cui 1,  Shuang Zhao 1,  Hui Chen 1,  Yuhan Fu 1,  Kai Han 1,  Shutao Yin 2,  Chong Zhao 1,  Lihong Fan 3,  Hongbo Hu 4
Affiliations

Affiliations

  • 1 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.
  • 2 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: [email protected].
  • 3 College of Veterinary Medicine, China Agricultural University, No.2 Yunamingyuan West Road, Haidian District, Beijing 100193, China. Electronic address: [email protected].
  • 4 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: [email protected].
PMID: 37481142 DOI: 10.1016/j.bcp.2023.115690
Abstract

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.

Keywords

Asparagine; Gefitinib resistance; MET; Methylseleninic acid; NSCLC.

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