Abstract
Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignancy that arises in the epithelial cells of the nasopharynx [1]
These results demonstrated that linsitinib suppressed cell proliferation and ionizing radiation (IR) can over activate insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, suggesting that phosphorylated IGF-1R (pIGF-1R) is an operative receptor in NPCs
Linsitinib completely conceal the effect of IGF-I-induced phosphorylation of IGF-1R, ERK, and Akt in NPCs, which might be linked with cell proliferation. These findings suggested that the IGF-I/IGF-1R signaling pathway is critical for cell proliferation in NPCs and linsitinib could effectively block IGF-I/IGF-1R signaling pathway, inhibiting mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways
Summary
Nasopharyngeal carcinoma (NPC) is a malignancy that arises in the epithelial cells of the nasopharynx [1]. Radiotherapy, and intensity-modulated radiotherapy (IMRT) have shown optimistic outcomes for NPC patient, with fiveyear overall survival (OS) 71%, 73%, and 80%, respectively [5]. There are still 20-30% NPC patient suffering from local recurrence and short-term disease out control after IMRT [6]. The development of molecular-targeted therapy over the past decades provides a beneficial option for NPC treatment. Some reagents, such as the anti-EGFR antibody, cetuximab, Mediators of Inflammation the anti-VEGF antibody, and bevacizumab, have been subjected to clinical usage against NPC [8, 9]. High incidence of grade 3-4 mucositis (87%) and grade 3 radiotherapy-related dermatitis (20%) has been observed in NPC patients treated with cetuximab [11]. Finding new regimen to provide effective therapeutics is of great need for NPC treatment
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