Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia condition

Abstract

Background & Aims: Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application, and the underlying mechanisms remain unclear. The aims of this study is to elucidate the role of abnormal signal transmission and metabolism in chemoresistance of OSCC under oxygen-deprived microenvironment, and try to find targeted drugs that enhance the sensitivity of DDP chemotherapy. Methods: Upregulated genes in OSCCs were determined by RNA-seq, public database, IHC, rt-qPCR and Western blotting (WB). The clinicopathological significance of IGF1R, ASS1, PYCR1 in OSCC were analyzed using Tissue Micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP resistance role of IGF1R, ASS1, PYCR1 in OSCC was investigated in vitro and in vivo. Results: Generally, tumor cells are in a hypoxic microenvironment. By genomic profiling, we identified IGF1R as one of RTKs, were upregulated in OSCCs under low oxygen condition. Clinically, enhanced IGF1R expression was associated with higher stages and poor prognosis in OSCC patients, and it’s inhibitor linsitinib, showed synergistic effects on DDP therapy in vivo and in vitro.Since hypoxia conditions frequently lead to metabolic reprogramming, we further integrated metabolomic analysis to find that abnormal IGF1R pathways promoted the expression of metabolic enzymes argininosuccinate synthetase 1 (ASS1) and pyrroline-5-carboxylate reductase 1 (PYCR1) via transcriptional activity of cMYC. Deeply, enhanced expression of ASS1 promoted arginine metabolism for biological anabolism, whereas PYCR1 activated proline metabolism for redox balance, which maintained the proliferation ability of OSCC cells during DDP treatment under hypoxia condition. Conclusions: Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under low oxygen conditions. Linsitinib targeting IGF1R signaling may provides promising combination therapy options for OSCC patients with DDP resistance.