Emerging Metabolic Targets in Cancer Therapy
Yuhua Zhao1, Hao Liu1, Adam I Riker2, Oystein Fodstad3, Susan P Ledoux4, Glenn L Wilson4, Ming Tan1,4
1
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA, 2Ochsner Health System, Ochsner Cancer Institute, Department of Surgery, New Orleans, LA 70121, USA, 3Institute for Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway, 4Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, AL 36608, USA
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. The energy requirements for tumor cell survival
- 4. The metabolic requirements of tumor cell proliferation
- 5. Metabolism-regulating signaling molecules, enzymes and transcription factors
- 5.1. PI3K-Akt-mTOR pathway
- 5.2. Hypoxia-inducible factor 1 (HIF-1)
- 5.3. c-Myc
- 5.4. Metabolic enzymes
- 5.4.1. Hexokinase (HK)
- 5.4.2. Pyruvate kinase (PK)
- 5.4.3. Lactate dehydrogenase (LDH)
- 5.4.4. Pyruvate dehydrogenase kinase (PDK)
- 5.4.5. Succinate dehydrogenase (SDH)
- 5.4.6. Fumarate hydratase (FH)
- 5.4.7. Isocitrate dehydrogenase 1 (IDH1)
- 6. p53
- 7. HSF1
- 8. Therapeutic implications in cancer therapy
- 8.1. Inhibition of metabolic enzymes
- 8.1.1. HK inhibitors
- 8.1.2. PKM2 inhibition
- 8.1.3. PDK inhibitors
- 8.2. Inhibition of metabolism-regulating signaling pathways
- 8.2.1. Inhibition of HIF-1αsignaling pathway
- 8.2.2. Inhibition of the PI3K-Akt-mTOR pathway
- 8.2.2.1. PI3K inhibitors
- 8.2.2.2. Akt inhibitors
- 8.2.2.3. mTOR inhibitors
- 8.2.2.4. Dual PI3K/mTOR inhibitors
- 8.2.2.5. AMPK activator
- 9. Targeting the Warburg effect may overcome tumor drug resistance
- 10. Future directions
- 11. Acknowledgements
- 12. References
1. ABSTRACT
Cancer cells are different from normal cells in their metabolic properties. Normal cells mostly rely on mitochondrial oxidative phosphorylation to produce energy. In contrast, cancer cells depend mostly on glycolysis, the aerobic breakdown of glucose into ATP. This altered energy dependency is known as the "Warburg effect" and is a hallmark of cancer cells. In recent years, investigating the metabolic changes within cancer cells has been a rapidly growing area. Emerging evidence shows that oncogenes that drive the cancer-promoting signals also drive the altered metabolism. Although the exact mechanisms underlying the Warburg effect are unclear, the existing evidence suggests that increased glycolysis plays an important role in support malignant behavior of cancer cells. A thorough understanding of the unique metabolism of cancer cells will help to design of more effective drugs targeting metabolic pathways, which will greatly impact the capacity to effectively treat cancer patients. Here we provide an overview of the current understanding of the Warburg effect upon tumor cell growth and survival, and discussion on the potential metabolic targets for cancer therapy.
