Antitumor Effects of Metformin in Squamous Cell Carcinoma under Leptin Treatment Conditions.

Abstract

Sinonasal squamous cell carcinoma (SNSCC) is a rare, aggressive malignancy with poor clinical outcomes. Metabolic syndrome components, including obesity-associated hyperleptinemia, may promote tumor progression. Leptin is an adipokine that is elevated in obesity and activates oncogenic pathways that drive cancer cell proliferation. Although metformin exhibits anticancer effects in various malignancies, its specific role in SNSCC remains unclear. In this study, we examined the effects of leptin on SNSCC progression and the anticancer mechanisms of metformin in RPMI 2650 cells. We measured cell viability, proliferation, colony formation, and apoptosis following leptin and/or metformin exposure. Mitochondrial membrane potential assays and Ki-67 immunocytochemistry were used to assess mitochondrial function and proliferation, respectively. The results indicated that leptin promotes RPMI 2650 cell proliferation, colony formation, and survival by activating extracellular signal-regulated kinase (ERK) signaling. Conversely, metformin inhibited these leptin-induced oncogenic effects by suppressing ERK phosphorylation, reducing proliferation (confirmed by Ki-67 analysis), and inducing apoptosis. Metformin also modulated the tumor microenvironment by upregulating interleukin (IL)-2 and IL-18, while downregulating Serpin E1/plasminogen activator inhibitor-1, to potentially enhance the antitumor immune response. Furthermore, metformin induced mitochondrial dysfunction, reducing the membrane potential and inducing apoptosis. The results indicate that leptin is a potential driver of SNSCC progression and establish the antiproliferative and proapoptotic effects of metformin through the induction of mitochondrial dysfunction and ERK pathway inhibition. The ability of metformin to counteract leptin-driven tumor growth suggests its potential therapeutic use against SNSCC, particularly in patients with metabolic disorders.