Abstract
BackgroundMost 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.ResultsHK2 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.ConclusionsThese results established HK2 as an effective therapeutic target even for cisplatin-resistant ovarian cancer and suggested a promising targeted therapeutic approach.
Highlights
We further evaluated their effects on the glucose metabolism pattern, reversal of cisplatin resistance, and antitumor effects in vitro and in vivo
Expression of follicle-stimulating hormone receptor (FSHR) and HK2 in A2780 and A2780CP ovarian cancer cells To screen the appropriate cell lines, we detected the expression of FSHR and HK2 in A2780, A2780CP human ovarian cancer cells and other control cancer cell lines
Higher expression of FSHR mRNA was observed in ovary than in other healthy tissues, suggesting that FSHR is an ideal target for ovarian cancer-specific drug delivery system
Summary
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. 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. Over 80% of patients are diagnosed with advanced-stage disease, and patients have a 10-year survival of only 15% [2]. The standard treatment for ovarian cancer is cytoreductive surgery followed by platinum-based chemotherapy. Chemoresistance occurs in 80–90% of patients with advanced-stage disease [3]. There is a critical need to develop therapeutic strategies to overcome chemoresistance
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