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Glycolosis, cancer and metabolomics


The cancer meeting
James Watson Scientist
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And so the cancer meeting turned out to be good and I think I chose the right title, "How will we cure most cancers?" So a number of people came and I think at the end of the meeting, I had, you know, talking about drug development and used in combinations that there was hope. And I think the chief reason for the hope is that attention has turned back to Otto Warburg's observation of lactic acid production in tumor tissue. And the significance was that increased glycolysis or diminished oxidation that lay at the root of it. And so I'm now almost manic about it, you know, manic in the sense that I think about it at night. You know, that we should just move fast, you know, perhaps we can, you know, I'll probably die of cancer unless someone gets a cure for it. So what seems to be, you know, the - and this comes out in part from the work of an old-fashioned biochemist named Peter Peterson at Johns Hopkins, whose work was post-doc with Albert Lehninger whose, you know, goal in life was finding the enzymes for oxidative phosphorylation, you know, until Peter Mitchell came along and said that you're not going to find enzymes, you're going to find pores and the whole proton pump thing. And - but he studied the Warburg Effect and the conclusion was that glycolysis runs much faster, maybe at least ten times faster in a growing cell, and that the cancer cell is just a growing cell, it doesn't have a distinctive biochemistry except for those that initiate, but the most important thing during growth is to make the precursors so that you can make the new molecules. The function of main use of glucose is not to make energy but just to provide two or three carbon intermediates which can then be used to build back big molecules and that energy production is, you know, the ATP made during glycolysis is pretty irrelevant because oxidative phosphorylation makes so much. So that's a key event in cancer cells is turning on glycolysis or in dividing cells. And one of the - now the best known signal I think is hypoxy-inducing factor, a transcription factor, which is normally a very unstabilized molecule but through a clever pathway it was stabilized in dimoriasis [?] with another relative and jumps on the DNA and turns on a number of enzymes, including a glucose transporter which brings the glucose into the cell and the amount of the glycolytic enzymes go up. And I think this is probably now a solid fact. And then Lew Cantley in his lab, Matthew Vanderheiden and the - another post-doc named Christophe that I didn't meet, made the, I think, very important observation that in growing cells, in cancer cells, the pyruvate kinase is spliced differently, the template for it, and that you get a splice variant found only in dividing cells. And this enzyme is inhibited by phosphotyrosines, which are sort of - signals for growth. So when you turn on, a hormone or something turns on a start of a signal to divide, phosphotyrosines appear. They block the pyruvate kinase and so the intermediates instead of being converted into pyruvate, get shunted off into the pentose phosphate shunt and used to make nucleotides, lipids, and so on. So there - is a few essential differences. The hexokinase Peterson showed translocates in the dividing cells to the surface of the mitochondria and attaches to the proton pump. So when the ATP would come out, it would immediately be seized by the hexokinase and glucose phosphorylate. So I think - and then Peterson found or one of his students had a molecule, 3-bromopyruvate, which they say inhibits hexokinase 2, which really stops the growth of hepatocellular carcinoma. You could say, well, stopping glycolysis, how would our heart beat and you're cutting off - and the answer is, you can do it. So you can, by a certain amount of inhibition of of glycolysis, the cells go into apoptosis. So you can sort of say that if a cell is halfway through cell division and suddenly doesn't have energy to complete it, the organism just sends out a signal to kill the cell rather than have a damaged cell around. That's sort of trying to make apoptosis look, you know, functional. There's the problem that, you know, if it kills all dividing cells, what do you do with the non-dividing cancer stem cells? You know, they may be there, but it might be enough that if you reduce the tumor to a really small size then the immunological responses against cancer cells which we know exist would be sufficient to kill it. So I think, again, you know, if someone told me I had a cancer that can't be cured, why not try a glycolytic thing? So Cantley and Craig Thompson from Penn and Vanderheiden formed a company to try and exploit inhibiting glycolysis and I'm told they've been quite successful in raising money to get it going.

American molecular biologist James Dewey Watson is probably best known for discovering the structure of DNA for which he was jointly awarded the 1962 Nobel Prize in Physiology or Medicine along with Francis Crick and Maurice Wilkins. His long career has seen him teaching at Harvard and Caltech, and taking over the directorship of Cold Spring Harbor Laboratory in New York. From 1988 to 1992, James Watson was head of the Human Genome Project at the National Institutes of Health. His current research focuses on the study of cancer.

Listeners: Walter Gratzer Martin Raff

Walter Gratzer is Emeritus Professor of Biophysical Chemistry at King's College London, and was for most of his research career a member of the scientific staff of the Medical Research Council. He is the author of several books on popular science. He was a Postdoctoral Fellow at Harvard and has known Jim Watson since that time

Martin Raff is a Canadian-born neurologist and research biologist who has made important contributions to immunology and cell development. He has a special interest in apoptosis, the phenomenon of cell death.



Listen to Martin Raff at Web of Stories



Duration: 8 minutes, 56 seconds

Date story recorded: November 2008 and October 2009

Date story went live: 18 June 2010