J Bioenerg Biomembr. 2007 Jun;39(3):211-22.    http://www.ncbi.nlm.nih.gov/pubmed/17879147

Warburg, me and Hexokinase 2: 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.

Abstract

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.

The “Warburg effect” likely provides the vast majority of cancerous tumors that exhibit this phenotype with a number of benefits.  One is biosynthesis.  A rapidly dividing cancer cell needs carbon precursors that are involved in the biosynthesis of cell building blocks.   The glycolytic pathway and its off-shoot the pentose phosphate pathway (hexose monophosphate shunt) are rich sources of precursors essential for the biosynthesis of nucleic acids, phospholipids, fatty acids, cholesterol, and porphyrins.    Thus maintain a high glycolytic rate within each tumor cell of a given tumor, even in the presence of oxygen (i.e., the “Warburg effect”) assures not only the tumor’s survival but its rapid growth.  A second advantage of the “Warburg effect” is likely involved in both tumor protection and invasion.   As tumor cells via glycolysis even in the presence of ozxygen produce latic acid and transport it out, this acid (i.e., its low pH) may both protect tumors (that are resistant to it) against attack by the immune system while inducing negative effects (chemical warfare) on normal surrounding cells, thus preparing them for invasion.  Finally, and not least important, the “Warburg effect also assures a longer tumor survival time if oxygen become limiting.    http://link.springer.com/article/10.1007/s10863-007-9094-x#page-2