Abstract
Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), the main source of fructose-2,6-bisphosphate, controls the first committed step in glycolysis. We investigate the clinical significance and roles of PFKFB3 in ovarian cancer using in vitro and in vivo experiments. We demonstrate that PFKFB3 is widely overexpressed in ovarian cancer and correlates with advanced stage/grade and poor outcomes. Significant up-regulation of PFKFB3 was found in ascites and metastatic foci, as well as CSC-enriched tumorspheres and ALDH+CD44+ cells. 3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. Blockade of PFKFB3 by siRNA approach in the CSC-enriched subset led to decreases in glycolysis and CSC properties, and activation of the NF-κB cascade. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer.
Highlights
Ovarian cancer is the leading cause of death in gynecologic malignancies with 75% of patients presenting late at the advanced stages
Overexpression of PFKFB3 in ovarian cancer correlates with metastasis and poor prognosis to study the role of PFKFB3 in ovarian cancer, we analyzed two independent microarray databases from Oncomine
13 pairs of FFPE tissue sections composed of metastatic foci and matched primary ovarian tumors were examined through PFKFB3 staining with IHC (Figure 1C)
Summary
Ovarian cancer is the leading cause of death in gynecologic malignancies with 75% of patients presenting late at the advanced stages. Because of the lack of an anatomical barrier, ovarian cancer cells are likely to separate from the primary lesion, shed and flow into the abdominal cavity and spread via the peritoneal fluid which allows cancer cells to spread into the distant organs [2]. Most advanced ovarian cancer patients are diagnosed with accumulation of peritoneal fluid ( known as ascites fluid). Previous studies have indicated that “spheroids” or “tumorspheres” can be enriched in ascites from patients with ovarian cancer with enhanced tumorigenesis and cancer stem cell (CSC) properties [3, 4]. Accumulating evidence suggests that CSCs or tumor-initiating cells may be the source of all tumor cells and a cause of metastasis, chemoresistance and recurrence [5]. Targeting CSCs may be a novel therapeutic strategy for ovarian cancer
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