Enhanced Antitumor Effects of Follicle-Stimulating Hormone Receptor-Mediated Hexokinase-2 Depletion on Ovarian Cancer Mediated by A Shift in Glucose Metabolism

Abstract

Background: Most cancers favor glycolytic-based glucose metabolism. Hexokinase-2 (HK2), the first glycolytic rate-limiting enzyme, shows limited expression in normal adult tissues but is overexpressed in many tumor tissues, including ovarian cancer. HK2 has been shown to be correlated with the progression and chemoresistance of ovarian cancer and could be a therapeutic target. However, the systemic toxicity of HK2 inhibitors has limited their clinical use. Since follicle-stimulating hormone (FSH) receptor (FSHR) is overexpressed in ovarian cancer but not in nonovarian healthy tissues, we designed FSHR-mediated nanocarriers for HK2 shRNA delivery to increase tumor specificity and decrease toxicity. Results: HK2 shRNA was encapsulated in a polyethylene glycol-polyethylenimine copolymer modified with the FSH β 33-53 or retro-inverso FSH β 33-53 peptide. The nanoparticle complex with FSH peptides modification effectively depleted HK2 expression and facilitated a shift towards oxidative glucose metabolism, with evidence of increased oxygen consumption rates, decreased extracellular acidification rates, and decreased extracellular lactate and glucose consumption in A2780 ovarian cancer cells and cisplatin-resistant A2780CP counterpart cells. Consequently, cell proliferation, invasion and migration were significantly inhibited, and tumor growth was suppressed even in cisplatin-resistant ovarian cancer. No obvious systemic toxicity was observed in mice. Moreover, the nanoparticle complex modified with retro-inverso FSH peptides exhibited the strongest antitumor effects and effectively improved cisplatin sensitivity by regulating cisplatin transport proteins and increasing apoptosis through the mitochondrial pathway. Conclusions: These results established HK2 as an effective therapeutic target even for cisplatin-resistant ovarian cancer and suggested a promising targeted therapeutic approach.

The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers

“…Specifically, cancer cells exhibit metabolic reprogramming such as dysregulated glucose uptake, excessive lipid synthesis and glutaminolysis [ 110 ]. These transformations are essential parameters in the maintenance and development of malignant phenotypes in harsh microenvironments [ 111 – 115 ]. The role of IGF2BP2 in glucose tolerance, insulin sensitivity, fatty acid oxidation and the development of metabolic diseases had been reviewed recently [ 13 , 21 – 23 , 28 , 53 ].…”