Enhanced antitumor effects of follicle-stimulating hormone receptor-mediated hexokinase-2 depletion on ovarian cancer me
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Journal of Nanobiotechnology Open Access
RESEARCH
Enhanced antitumor effects of follicle‑stimulating hormone receptor‑mediated hexokinase‑2 depletion on ovarian cancer mediated by a shift in glucose metabolism Meng Zhang1†, Qiyu Liu1†, Mingxing Zhang1, Cong Cao2, Xiaoxia Liu1, Mengyu Zhang1, Guiling Li1, Congjian Xu1,3* and Xiaoyan Zhang1*
Abstract Background: Most cancers favor glycolytic-based glucose metabolism. Hexokinase-2 (HK2), the first glycolytic ratelimiting 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 cisplatinresistant 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. Keywords: Ovarian carcinoma, Hexokinase-2, Targeted therapy, Chemoresistance, Follicle-stimulating hormone
*Correspondence: [email protected]; [email protected] † Meng Zhang and Qiyu Liu equally contributed to this work 1 Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this a
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