TY - JOUR
T1 - Warburg, me and Hexokinase 2
T2 - Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen
AU - Pedersen, Peter L.
N1 - Funding Information:
Acknowledgements The author is most grateful for support from the NIH via research grants CA 80018 and CA 10951 and to Dr. Young Ko for her many helpful discussions related to the manuscript and her research on both the ATP synthasome and cancer. David Blum, a predoctoral student in the Department of Biological Chemistry and a medical illustrator is gratefully acknowledged for his help in preparing the figure. The author is grateful also to the Nobel Foundation for permission to use the photograph of Otto Warburg, and to Elsevier for permission to reproduce Figure 4 and Figure 5 in the supplement to the article by Ko, Y. H., Smith, B.L., Wang, Y., Pomper, M.G., Rini, D. A., Torbenson, M. S., Hullihen, J., and Pedersen, P. L. (2004) “Advanced Cancers: Eradication in all cases using 3-bromopyruvate therapy to deplete ATP”. Biochem. Biophys. Res. Commun. Nov. 5, 324(1):269-75, Copyright 2004.
PY - 2007/6
Y1 - 2007/6
N2 - As a new faculty member at The Johns Hopkins University, School of Medicine, the author began research on cancer in 1969 because this frequently fatal disease touched many whom he knew. He was intrigued with its viscous nature, the failure of all who studied it to find a cure, and also fascinated by the pioneering work of Otto Warburg, a biochemical legend and Nobel laureate. Warburg who died 1 year later in 1970 had shown in the 1920s that the most striking biochemical phenotype of cancers is their aberrant energy metabolism. Unlike normal tissues that derive most of their energy (ATP) by metabolizing the sugar glucose to carbon dioxide and water, a process that involves oxygen-dependent organelles called "mitochondria", Warburg showed that cancers frequently rely less on mitochondria and obtain as much as 50% of their ATP by metabolizing glucose directly to lactic acid, even in the presence of oxygen. This frequent phenotype of cancers became known as the "Warburg effect", and the author of this review strongly believed its understanding would facilitate the discovery of a cure. Following in the final footsteps of Warburg and caught in the midst of an unpleasant anti-Warburg, anti-metabolic era, the author and his students/collaborators began quietly to identify the key molecular events involved in the "Warburg effect". Here, the author describes via a series of sequential discoveries touching five decades how despite some impairment in the respiratory capacity of malignant tumors, that hexokinase 2 (HK-2), its mitochondrial receptor (VDAC), and the gene that encodes HK-2 (HK-2 gene) play the most pivotal and direct roles in the "Warburg effect". They discovered also that like a "Trojan horse" the simple lactic acid analog 3-bromopyruvate selectively enters the cells of cancerous animal tumors that exhibit the "Warburg effect" and quickly dissipates their energy (ATP) production factories (i.e., glycolysis and mitochondria) resulting in tumor destruction without harm to the animals.
AB - As a new faculty member at The Johns Hopkins University, School of Medicine, the author began research on cancer in 1969 because this frequently fatal disease touched many whom he knew. He was intrigued with its viscous nature, the failure of all who studied it to find a cure, and also fascinated by the pioneering work of Otto Warburg, a biochemical legend and Nobel laureate. Warburg who died 1 year later in 1970 had shown in the 1920s that the most striking biochemical phenotype of cancers is their aberrant energy metabolism. Unlike normal tissues that derive most of their energy (ATP) by metabolizing the sugar glucose to carbon dioxide and water, a process that involves oxygen-dependent organelles called "mitochondria", Warburg showed that cancers frequently rely less on mitochondria and obtain as much as 50% of their ATP by metabolizing glucose directly to lactic acid, even in the presence of oxygen. This frequent phenotype of cancers became known as the "Warburg effect", and the author of this review strongly believed its understanding would facilitate the discovery of a cure. Following in the final footsteps of Warburg and caught in the midst of an unpleasant anti-Warburg, anti-metabolic era, the author and his students/collaborators began quietly to identify the key molecular events involved in the "Warburg effect". Here, the author describes via a series of sequential discoveries touching five decades how despite some impairment in the respiratory capacity of malignant tumors, that hexokinase 2 (HK-2), its mitochondrial receptor (VDAC), and the gene that encodes HK-2 (HK-2 gene) play the most pivotal and direct roles in the "Warburg effect". They discovered also that like a "Trojan horse" the simple lactic acid analog 3-bromopyruvate selectively enters the cells of cancerous animal tumors that exhibit the "Warburg effect" and quickly dissipates their energy (ATP) production factories (i.e., glycolysis and mitochondria) resulting in tumor destruction without harm to the animals.
KW - "Warburg effect"
KW - 3-bromopyruvate
KW - Cancer
KW - Cancer therapy
KW - Drug target
KW - Glycolysis
KW - Hexokinase 2
KW - Mitochondria
KW - Positron emission tomography (PET)
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U2 - 10.1007/s10863-007-9094-x
DO - 10.1007/s10863-007-9094-x
M3 - Review article
C2 - 17879147
AN - SCOPUS:35448964610
SN - 0145-479X
VL - 39
SP - 211
EP - 222
JO - Journal of Bioenergetics and Biomembranes
JF - Journal of Bioenergetics and Biomembranes
IS - 3
ER -