Tumor metabolism regulating chemosensitivity in ovarian cancer

Abstract

Elevated metabolism is a key hallmark of multiple cancers, serving to fulfill high anabolic demands. Ovarian cancer (OVCA) is the fifth leading cause of cancer deaths in women with a high mortality rate (45%). Chemoresistance is a major hurdle for OVCA treatment. Although substantial evidence suggests that metabolic reprogramming contributes to anti-apoptosis and the metastasis of multiple cancers, the link between tumor metabolism and chemoresistance in OVCA remains unknown. While clinical trials targeting metabolic reprogramming alone have been met with limited success, the synergistic effect of inhibiting tumor-specific metabolism with traditional chemotherapy warrants further examination, particularly in OVCA. This review summarizes the role of key glycolytic enzymes and other metabolic synthesis pathways in the progression of cancer and chemoresistance in OVCA. Within this context, mitochondrial dynamics (fission, fusion and cristae structure) are addressed regarding their roles in controlling metabolism and apoptosis, closely associated with chemosensitivity. The roles of multiple key oncogenes (Akt, HIF-1α) and tumor suppressors (p53, PTEN) in metabolic regulation are also described. Next, this review summarizes recent research of metabolism and future direction. Finally, we examine clinical drugs and inhibitors to target glycolytic metabolism, as well as the rationale for such strategies as potential therapeutics to overcome chemoresistant OVCA.

Keywords: chemoresistance; hexokinase 2; ovarian cancer; p53; tumor metabolism.

Figure 1. Reprogramming tumor metabolism in chemoresistant OVCA

Metabolic reprogramming of cancer cells contributes to their transformation. The Warburg effect (see main text) often allows cancerous cells to maintain energy production in otherwise energy poor conditions. Genetic and environmental factors may transform normal cells to either chemosensitive or chemoresistant OVCA. However, the majority of chemoresistant cells stem from chemosensitive cancer cells that acquire their resistance due to multiple factors: increased DNA Repair, CDDP detoxification, increased metabolism, and the upregulation of multi-drug resistance and copper transporters. As a result, chemoresistant cells have markedly higher rates of proliferation, and their metabolism is less sensitive to bouts of chemotherapeutics. We and other, have also demonstrated that the recovery of defective p53 and PTEN can sensitize chemoresistant cells to chemotherapy.

Figure 2. The regulation of HKII and other glycolytic enzymes in ovarian cancer cells

Enhanced glycolysis in cancer cells, through a combination of metabolic pathways, drives glucose utilization to fulfill high anabolic demands. In this schematic diagram of the glycolysis pathway, metabolites are shown as square boxes. Key regulatory molecules which either promote (yellow box) or suppresses (purple box) glycolytic enzymes and metabolites such as G-6-P are shown. GLUT (glucose transporter), G-6-P (glucose-6-phosphate), F-6-P (fructose-6-phosphate), F-1,6-BP (fructose-1,6-bisphosphate), G-3-P( glyceraldehyde 3-phosphate), 1,3-BPG (1,3-bisphosphoglycerate), 2-PG (2-phosphoglycerate), 3-PG (3-phophosphoglycerate); PEP (phosphoenolpyruvate), PFK (phosphofructokinase), GAPDH (glyceraldehyde 3-phosphate dehydrogenase), TIGAR (TP53-inducible glycolysis and apoptosis regulator), ENO (enolase), MCT (monocarboxylate transporter). mTORC1 (mTOR complex 1), Mutant p53 (defect p53), PFKFB (6‑phosphofructo 2‑kinase/fructose‑2,6‑bisphosphatase), Akt (Protein Kinase B), HIF-1α (hypoxia Inducible Factor-1α), c-Myc (v-myc avian myelocytomatosis viral oncogene homolog), and LPA (Lysophosphatidic acid).

Figure 3. Mitochondrial-HKII drives chemoresistance in OVCA

A hypothetical model demonstrating mechanisms regulating the mitochondrial localization of HK II and apoptosis. A. In chemosensitive OVCA cells, CDDP-induced detachment of mitochondrial bound HK II (mito-HKII) from VDAC is required for the induction of apoptosis. Chemotherapy such as CDDP induces the phosphorylation of p53 at Ser 15 (S15) and Ser 20 (S20), which suppresses phosphorylation of Akt, and promotes binding of HKII to mitochondria. In the absence of mito-HKII, proapoptotic Bcl-2 family proteins (Bax and Bad) interact with VDAC, increasing MPTP, ROS, MOMP, and Ca²⁺ in the OMM where AIF and cytochrome c are released. B. In chemoresistant OVCA cells, CDDP-induced apoptosis is attenuated due to defective p53. Through increased GLUT1 & 3 membrane trafficking, glucose is transported into the cell. Activated PI3-kinase phosphorylates lipids in the plasma membrane where Akt is recruited for activation. Activated Akt phosphorylates HKII (P-HKII), facilitates the translocation of Bcl-X_L and promotes binding of P-HKII to VDAC on the OMM, thus preventing apoptosis. Bcl-X_L directly interacts with VDAC, closing the mitochondrial ion channel and decreasing MOMP, while HKII inhibits apoptosis by competing for the binding sites for Bax and Bad of VDAC [26].