Abstract

Purpose: The acquired resistance to erlotinib, an EGFR tyrosine kinase inhibitor (EGFR-TKI), is a great challenge in the targeted therapy of non-small cell lung cancer (NSCLC). Targeting glutamine import could re-sensitize the resistant cancer cells to erlotinib. Our results indicated that the glutamine transporter solute carrier 1 family member  5 (SLC1A5) could be a potential target for the treatment of NSCLC, and the application of GPNA, an SCL1A5 inhibitor, may reverse the acquired resistance to erlotinib.

Materials and Methods: The cell proliferation was measured by crystal violet staining assay. The expression levels of proteins were checked by western blot. The flow cytometry was used to analyze the cell cycle. CO-IP was used to detect the ubiquitination of indicated proteins.

Results: The expression of SLC1A5 in erlotinib-resistant cell lines (PC9ER, HCC827ER) was significantly higher than those in the erlotinib-sensitive cell lines (PC9, HCC827). The proliferation of erlotinib-resistant cells was more dependent on glutamine. Inhibition of SLC1A5 significantly suppressed the growth of NSCLC cells, especially for the erlotinib-resistant cells. Moreover, inhibition of SLC1A5 aggravated the inhibitory efficacy of erlotinib on cell proliferation in erlotinib-resistant cells and induced cell cycle arrest in G0/G1 phase. Mechanistically, SLC1A5 inhibition facilitated PDK1 degradation through the ubiquitin-proteasome pathway, and decreased the expression of p-AKT, Cyclin B1 and CDC42.

Discussion: Glutamine and its transporters play important roles in the development of various numbers of cancers. In this study, we showed that the proliferation of erlotinib resistance NSCLC cells exhibited greater dependence on glutamine. Our study highlighted the role of SLC1A5 in promoting the proliferation of NSCLC cells, especially in erlotinib-resistant NSCLC cells. The effect of SLC1A5 on cell growth in NSCLC was related with its metabolism regulation function and its impact on PDK1-AKT signaling pathway. Our results indicated that SLC1A5 would be a potential target for the treatment of EGFR-TKIs resistant NSCLC.