Abstract
Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.
Highlights
Ovarian cancer is the most lethal of all gynecological malignancies worldwide [1]
Moderate to strong Hexokinase 2 (HK2) protein was localized in the cytoplasm in ovarian cancer samples; in contrast, it was barely detectable in benign cystadenomas
We found that ectopic expression of HK2 enhanced cell migration and invasion (Figure 3B), as well as increased focal adhesion kinase (FAK) and ERK1/2 activation (Figure 3C), along with increased matrix metalloproteinase 9 (MMP9), urokinase-type plasminogen (uPA) and Vascular endothelial growth factor (VEGF) mRNA expression (Figure 3D)
Summary
Ovarian cancer is the most lethal of all gynecological malignancies worldwide [1]. Its high mortality is mainly due to the late presentation of symptoms at the advanced stages of the disease, often once the cancer has metastasized [2,3]. Primary treatment mainly involves cytoreductive surgery followed by adjuvant chemotherapy. Even with optimal treatment, recurrences are common, Cancers 2019, 11, 813; doi:10.3390/cancers11060813 www.mdpi.com/journal/cancers. Cancers 2019, 11, 813 and the overall prognosis is poor. Continued efforts to identify and develop new target therapies are, essential. As an intra-abdominal tumor, metastasis arises when exfoliated ovarian cancer cells that have detached from the primary tumor float in the peritoneal fluid and spread throughout the peritoneal cavity [3]
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