Metabolic reprogramming in epithelial ovarian cancer.

Am J Transl Res 2021;13(9):9950-9973 www.ajtr.org /ISSN:1943-8141/AJTR0134877 Review Article Metabolic reprogramming in epithelial ovarian cancer Chalaithorn Nantasupha1, Chanisa Thonusin2,3,4, Kittipat Charoenkwan1, Siriporn Chattipakorn3,4,5, Nipon Chattipakorn2,3,4 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 2Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 3Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 4Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand; 5Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand 1 Received May 1, 2021; Accepted July 12, 2021; Epub September 15, 2021; Published September 30, 2021 Abstract: Cancer cells usually show adaptations to their metabolism that facilitate their growth, invasiveness, and metastasis. Therefore, reprogramming the energy metabolism is one of the current key foci of cancer research and treatment. Although aerobic glycolysis-the Warburg effect-has been thought to be the dominant energy metabolism in cancer, recent data indicate a different possibility, specifically that oxidative phosphorylation (OXPHOS) is the more likely form of energy metabolism in some cancer cells. Due to the heterogeneity of epithelial ovarian cancer, there are different metabolic preferences among cell types, study types (in vivo/in vitro), and invasiveness. Current knowledge acknowledges glycolysis to be the main energy provider in ovarian cancer growth, invasion, migration, and viability, so specific agents targeting the glycolysis or OXPHOS pathways have been used in previous studies to attenuate tumor progression and increase chemosensitization. However, chemoresistant cell lines exert various metabolic preferences. This review comprehensively summarizes the information from existing reports which could together provide an in-depth understanding and insights for the development of a novel targeted therapy which can be used as an adjunctive treatment to standard chemotherapy to decelerate tumor progression and decrease the epithelial ovarian cancer mortality rate. Keywords: chemoresistance, chemosensitivity, epithelial ovarian cancer, glycolysis, oxidative phosphorylation Introduction Epithelial ovarian cancer (EOC) is one of the most common causes of cancer death in women for two main reasons: its most frequent presentation occurs at an advanced-stage and its high recurrence rate [1]. Despite the use of chemotherapy and targeted therapy, the ovarian cancer mortality rate remains as high as 70% [2]. The factors that affect the disease prognosis and survival of EOC are its invasiveness, metastatic properties, and treatment response [3, 4]. The extent of its invasiveness and metastatic properties reflect the staging of EOC [2]. As regards the treatment response, several factors can contribute to chemoresistance after a period of treatment for EOC, including an increased elimination of the active form of chemotherapy and the development of drug-resistant genes [5-7]. In the past decade, a new theory called “deregulation of cellular energetics” has been posited that focuses on the metabolic support of the growth, proliferation, invasion, and metastasis of cancer cells, and this has become one of the biological targets of cancer treatment development [8]. The Warburg effect, defined as the preference of cancer cells to use glycolysis even in the presence of oxygen, became one of those targets [9]. Prior studies demonstrated that the Warburg effect might be associated with the resistance of most cancer cells to treatment [10-12]. However, current evidence suggests that not every tumor exhibits the Warburg effect [13, 14]. EOC, a heterogeneous form of cancer, may use another pathway, such as oxidative phosphorylation (OXPHOS) [14, 15]. Apart from the current regimens of chemotherapy and targeted therapy, such as antiangio- Metabolic reprogramming in ovarian cancer genesis and poly-ADP ribose polymerase (PARP) inhibitors, a treatment that modulates cancer metabolism has been proposed to improve the treatment response of EOC [16-20]. In this review, we comprehensively summarize studies on the metabolic changes in EOC compared to normal ovarian cells from in vitro, in vivo and clinical studies. Consistencies and controversies from the reports on the metabolic characters that are associated with the invasiveness and chemoresistant properties of EOC, and the effects of metabolic interventions on EOC progression and treatment response are also summarized and discussed. This comprehensive review will enhance the fundamental overarching understanding pertinent to the metabolism of EOC and highlight mechanistic insights for the development of novel drug regimens to target this. Advances in drug therapies may assist in reducing the tumor invasiveness, the tumor metastasis, and the mortality rate of EOC via the metabolic pathways. Search strategy and selection criteria The PubMed database was searched using the keywords “ovarian cancers”, “glycolysis”, and “oxidative” from its inception to September 2020. The search was limited to original articles published in English. A general consideration of ovarian cancer metabolism regarding glycolysis and the oxidative phosphorylation pathway The pathways and regulation of glycolysis and OXPHOS are depicted in Figure 1. Under normal physiological conditions, glycolysis consists of a multistep pathway of glucose breakdown, followed by the conversion of phosphoenolpyruvate (PEP) to pyruvate via the enzyme pyruvate kinase M1 (PKM1). Pyruvate is then moved to the mitochondria and enters the tricarboxylic acid (TCA) cycle via mitochondrial pyruvate carrier 1 (MPC1). This is followed by a respiratory chain consisting of five complexes, resulting in the release of thirty-six ATP molecules per single glucose molecule [21]. In the mitochondria, OXPHOS occurs resulting in the production of ATP, the energy for this production [21]. Under hypoxic conditions, PEP is converted to pyruvate by pyruvate kinase M2 (PKM2), pyruvate is subsequently changed into lactate by lactate dehydrogenase (LDH) and 9951 moves out of the cells via monocarboxylate transporter 4 (MCT4) (Figure 1) [22]. Even under normoxic conditions, some cancer cells utilize glycolysis without any of the glucose residues entering the TCA cycle [22]. Since glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, glycolytic enzymes also support cell growth [8, 23]. For instance, hexokinase 2 (HK2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enzymes can regulate mTOR and apoptosis, while the phosphoglycerate mutase 1 (PGAM1) enzyme can induce the formation o (...truncated)