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The Mitochondrial Warburg Effect: A Cancer Enigma

  • Kim, Hans H. (Department of Chemistry, University of Pennsylvania) ;
  • Joo, Hyun (Department of Physiology and Integrated Biosystems, College of Medicine, Inje University) ;
  • Kim, Tae-Ho (Systems Immunology Laboratory, WPI Immunology Frontier Research Center, Osaka University) ;
  • Kim, Eui-Yong (Department of Physiology and Integrated Biosystems, College of Medicine, Inje University) ;
  • Park, Seok-Ju (Department of Internal Medicine, College of Medicine, Inje University and Busan Paik Hospital Organ Transplantation Center) ;
  • Park, Ji-Kyoung (Department of Pediatric Hematology-Oncology, College of Medicine, Inje University and Busan Paik Hospital) ;
  • Kim, Han-Jip (Department of Life Sciences, Ajou University)
  • Published : 2009.06.30

Abstract

"To be, or not to be?" This question is not only Hamlet's agony but also the dilemma of mitochondria in a cancer cell. Cancer cells have a high glycolysis rate even in the presence of oxygen. This feature of cancer cells is known as the Warburg effect, named for the first scientist to observe it, Otto Warburg, who assumed that because of mitochondrial malfunction, cancer cells had to depend on anaerobic glycolysis to generate ATP. It was demonstrated, however, that cancer cells with intact mitochondria also showed evidence of the Warburg effect. Thus, an alternative explanation was proposed: the Warburg effect helps cancer cells harness additional ATP to meet the high energy demand required for their extraordinary growth while providing a basic building block of metabolites for their proliferation. A third view suggests that the Warburg effect is a defense mechanism, protecting cancer cells from the higher than usual oxidative environment in which they survive. Interestingly, the latter view does not conflict with the high-energy production view, as increased glucose metabolism enables cancer cells to produce larger amounts of both antioxidants to fight oxidative stress and ATP and metabolites for growth. The combination of these two different hypotheses may explain the Warburg effect, but critical questions at the mechanistic level remain to be explored. Cancer shows complex and multi-faceted behaviors. Previously, there has been no overall plan or systematic approach to integrate and interpret the complex signaling in cancer cells. A new paradigm of collaboration and a well-designed systemic approach will supply answers to fill the gaps in current cancer knowledge and will accelerate the discovery of the connections behind the Warburg mystery. An integrated understanding of cancer complexity and tumorigenesis is necessary to expand the frontiers of cancer cell biology.

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