Identification of proteins related with pemetrexed resistance by iTRAQ and PRM-based comparative proteomic analysis and exploration of IGF2BP2 and FOLR1 functions in non-small cell lung cancer cells.

Pemetrexed (PEM), a multi-target folate antagonist, has been extensively used for the treatment of non-small cell lung cancer (NSCLC). However, the therapeutic efficacy of PEM is limited by tumor resistance. In this project, iTRAQ and parallel reaction monitoring (PRM)-based LC-MS/MS comparative proteomic analysis was performed to identify protein determinants of PEM resistance in A549/PEM cells versus A549 parental cells. A total of 567 differentially expressed proteins (DEPs) were identified by iTRAQ analysis. The function and classification of DEPs were analyzed through GO and KEGG Pathway databases. Moreover, PRM analysis further validated the expression changes of 14 DEPs identified by iTRAQ analysis. Moreover, insulin-like growth factor (IGF) 2 mRNA-binding protein 2 (IGF2BP2) or folate receptor alpha (FOLR1) knockdown weakened PEM resistance, reduced cell viability and promoted cell apoptosis in A549/PEM cells. IGF2BP2 depletion inhibited cell migration, invasion and epithelial-mesenchymal transition (EMT), while FOLR1 loss had no much effect on cell migration, invasion and EMT in A549/PEM cells. Our study can provide a deep insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules. SIGNIFICANCE: Our study can provide deeper insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules.