The members understand that the Warburg Effect refers to the preferential use of glycolysis for the production of ATP in cancer cells. The glycolytic pathway is very important for the growth of all cells. Although glycolysis only produces two molecules of ATP per molecule of glucose, respiration produces 30 molecules.
However, glycolysis, via the pentose monophosphate shunt, is essential for the production of nucleotides (DNA and RNA), phospholipids, fatty acids, and cholesterol. NADPH is produced by the pentose shunt. One of the roles of NADPH in the body is the regeneration of oxidized (inactive) glutathione into its reduced active form. Clearly, a rapid and sustained glycolysis is important for prolonged cellular growth.
Hexokinase 1/2 are the rate limiting enzymes for glycolysis. When glucose enters a cell, it is converted to glucose-6-phosphate by hexokinase. This compound, G6P, is converted into other molecules along the glycolytic and pentose shunt pathways. Interestingly, PET scans, using radioactive glucose molecules, in effect measure the activity of hexokinase enzymes in cancer cells.
Hexokinase is only stable if bound to the outer mitochondrial membrane. There are two reasons for this.
First, in order to produce large amounts of G6P hexokinase enzymes require a consistently available source of ATP, their energy source. ATP is synthesized in the inner mitochondrial membrane. This makes it readily available to hexokinase enzymes attached to the outer mitochondrial membrane.
Second, soluble hexokinase is feedback inhibited by its product, G6P. However, membrane bound hexokinase is unaffected by G6P.
Hexokinase-2 is substantially over expressed in virtually all cancer cells. The genetic factor that controls the synthesis of hexokinase is HIF-1, or hypoxia inducing factor. This makes perfect sense. When a tumor becomes deprived of oxygen, HIF-1 shifts the cellular metabolism to glycolysis, a metabolic pathway that does not require oxygen to function.
There is a direct link between the inhibition of glycolysis and the promotion of apoptosis. Interestingly, it has nothing to do with the accumulation of reactive oxygen radicals in the mitochondria during respiration.
Hexokinase 1/2 bind to a protein in the mitochondrial membrane called VDAC. VDAC is a global regulator of mitochondrial function. Anti-death proteins such as BCL-2 close the VDAC and inhibit apoptosis. Pro-death proteins such as Bax and Bak do the exact opposite, they open the VDAC thereby promoting the release of cytochrome C.
There is now evidence that the interaction between hexokinase and VDAC is THE critical regulator of mitochondrial stability. If hexokinase is dislodged from the mitochondrial VDAC protein, cytochrome C is released and apoptosis is initiated.
A brand new study has found that the release of hexokinase from the mitochondrial membrane triggers apoptosis independently of VDAC activity. This confirms that the association of hexokinase with the mitochrodrial membrane blocks apoptosis. When hexokinase is dislodged, the mitochondrial membrane undergoes conductibity changes which increases its permeability and promotes the release of cytochrome C.
The dislodged hexokinase also promotes necrosis by reducing the effectiveness of respiration and ATP synthesis. When bound hexokinase splits ATP, the ADP produced reenters the mitochondria to promote further respiration. ADP produced by soluble hexokinase does not do this.
HIF-1 stimulates the synthesis of hexokinase, but these enzymes are not biologically active. In order for hexokinase enzymes to associate with the VDAC outer membrane protein, the enzymes MUST be phosphorylated by the PI-3K/AKT signaling pathway. This explains how AKT can both promote glycolysis while concurrently inhibiting apoptosis.
Methyl jasmonate is a powerful initiator of cancer cell death. It does so by specifically interacting with the outer mitochondrial membranes of cancer but not normal cells. This results in a reducation of ATP synthesis and the initiation of necrosis and apoptosis.
A recent study found that methyl jasmonate directly bound hexokinase enzymes and detached them from the mitochondrial membrane. This accounts for the profound pro-apoptosis/necrosis inducing ability of methyl jasmonate.
Another study found that lithium also detached hexokinase from the mitochondrial membrane.
Methyl jasmonate is expensive, but lithium orotate is not. The combined synergistic use of these two agents could have a profound affect on the distruption of glycolysis and the promotion of programmed cell death (apoptosis and autophagy) and necrosis.
Summary
If glycolysis is inhibited, a cell will depend on respiration for the bulk of its ATP. ATP generated in the mitochondria produces superoxide anion, a highly reactive oxygen free radical. In order to neutralize this radical, reduced (active) glutathione must be actively transported into the mitochondria.
Glycolysis, via the pentose shunt, produces NADPH, a critically important co-factor for the synthesis of many pro-growth factors. In addition, NADPH controls, literally, the reducing potential of a cell via its ability to regenerate glutathione.
In past essays, we have attempted to block the uptake of glutathione into the mitochondria. In this essay, via the inhibition of hexokinase activity, we have discussed the inactivation of glycolysis and the pentose shunt. If NADPH synthesis is impaired, so is the synthesis of active glutathione, thereby rapidly promoting oxidation induced cellular death.
The synergistic use of methyl jasmonate, lithium and a few other goodies can induce necrosis, apoptosis and autophagy...and that ain't bad.
I am now completely rewriting the autophagy cytotoxic protocol. It will take me a few days. I intend to list the components in their order of importance.
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
http://www.grouppekurosawa.com
I've read where elevated HIF and hypoxia in prostate tumors is a negative prognosis.
Posted by: satx2 | April 29, 2008 at 08:43 AM
Elevated HIF-1 is associated with all cancers.
Posted by: Dr. Steve Martin | April 29, 2008 at 04:32 PM