added 2 research items
Abstract Mitotic tumor cells have to synthetize fatty acids and lipid membranes; fatty acid synthesis forms a malonylCoA intermediate, which inhibits the mitochondrial fatty acid carnityl transporter and closes automatically their degradation and beta-oxidation into acetylCoA. Since the glycolytic supply of acetylCoA is OFF as well, (a persistent phosphorylation inhibits pyruvate kinase and pyruvate dehydrogenase); tumor cells become vitally dependent of ketolysis and of the specific ketolytic enzyme: succinyl-CoA: 3-oxoacid-CoA transferase (SCOT) for making acetylCoA in their mitochondria. We discuss the supply of the two substrates driving this enzyme: the first, succinylCoA, in relation to succinodehydrogenase (SDH)-deficient cancers of the Carney Triad; and the second, acetoacetic acid, in relation to the ketogenic diet. Acetohydroxamic acid a non-toxic inhibitor for the ketolytic enzyme was in use for other medical indications; it may then block the tumor. Further, we earlier showed a regression of tumors after slowing down the citrate mitochondrial efflux, and inhibiting ATP citrate lyase, with lipoic acid-hydroxycitrate mixtures. However, tumor cells develop a salvage pathway by incorporating external acetate into the lipogenic pathway, via a cytosolic acetylCoA synthetase; allicine and orotic acid inhibit this enzyme. efficiently the ketolytic route for making acetylCoA in its mitochondria,
In tumor cells, ketolysis becomes the unique source of mitochondrial acetyl CoA. Indeed, the glycolytic acetyl CoA production is blocked (pyruvate kinase and pyruvate dehydrogenase are inhibited by phosphorylation). Whereas, the fatty acid degradation into acetyl CoA is also turned off by malonyl CoA, the product of acetyl CoA carboxylase, which forms with the synthesis of fatty acids, to automatically close down their degradation, by inhibiting the fatty acid mitochondrial transporter. Thus, inhibiting the ketolytic supply of acetyl CoA and the specific ketolytic enzyme: succinyl-CoA: 3-oxoacid-CoA transferase, should block the tumor. However, tumor cells are able to take-up acetate and convert it into acetyl CoA in their cytosol via an acetyl CoA synthetase and inhibiting this enzyme would make it difficult for tumor cells to survive.
Citation: Maurice Israël and Laurent Schwartz (2020) The metabolic rewiring observed in cancer renders tumor cells dependent of ketone bodies and vulnerable to SCOT inhibition. Endocrinol Diabetes Metab J Volume 4(1): 1-13 (2020). Abstract The finding that autoantibodies against glutamic acid decarboxylase that synthesizes GABA, provoke Diabetes type I, draws attention on a GABAergic regulation of the endocrine pancreas suppressing catabolic glucagon release if anabolic insulin is liberated; a GABA deficiency would then impair this exclusion mechanism, allowing a release of both hormones. Moreover, the GABA deficiency alters a mechanism terminating insulin release; an insulin leakage renders differentiated cells gradually resistant to insulin, while responding to glucagon. Mitotic cells with new insulin receptors, respond to both hormones, displaying a hybrid metabolic pattern typically found in tumor cells. They cannot get their mitochondrial acetyl CoA from glycolysis, since pyruvate kinase and pyruvate dehydrogenase are OFF, following the glucagon signal. Nor can they form acetyl CoA by the beta-oxidation of fatty acids, since the insulin signal they receive elicits the synthesis of fatty acids, which automatically closes their beta-oxidation. Indeed, malonyl CoA produced along the lipogenic pathway inhibits the mitochondrial carnityl-transporter of fatty acids. Hence, with both the glycolytic and fatty acid sources of mitochondrial acetyl CoA closed, tumor cells can only get their vital mitochondrial acetyl CoA supply from the ketolysis of ketone bodies. Maurice Israël (2020) The metabolic rewiring observed in cancer renders tumor cells dependent of ketone bodies and vulnerable to SCOT inhibition Endocrinol Diabetes Metab J, Volume 4(1): 2020 Differentiated tissues resistant to insulin, but responding to glucagon, adequately provide these ketone bodies. The enzyme, Succinyl-CoA: 3-oxoacid-CoA transferase (SCOT) is specific to ketolysis producing acetyl CoA. Its inhibition deprives tumor cell mitochondria of acetyl CoA, which should hold back tumor development. Inhibiting also the cytosolic acetyl CoA synthetase that tumor cells use for feeding their lipid synthesis should block the tumor.
The carcinogenic mechanism proposed considers that stem cells committed to repair tissues and differentiated cells, acquire different metabolic properties, if there is an associated GABA deficiency suppressing a control system of the endocrine pancreas. This control system mediated by GABA, released with insulin, normally turns off glucagon and somatostatin release when insulin is released. A consequence of the GABA deficiency in pancreas and adrenals is a hybrid insulin-glucagon-somatostatin message, received by new mitotic stem cells displaying then a hybrid metabolic rewiring. This gives them a selective metabolic advantage over differentiated cells that become insulin resistant and only receive the glucagon-somatostatin part of the hormonal message. Indeed, their insulin receptors are desensitized by the persistent leakage of insulin resulting from the GABA deficiency that fails to close the insulin release mechanism. Thus differentiated cells are simply rewired to be plundered by stem cells. The metabolic advantage gained by stem cells blocks their own differentiation and maintains their mitotic capacity. Inevitable mutations of mitotic cells follow, the immune system is unable to eliminate a geometrically increasing number of altered stem cells, a selection of the most aggressive but metabolically successful population takes place when cancer is declared.
Abstract In cancer, mitotic tumor cells display an active anabolic metabolism associated to a geometric increase of their number, while differentiated cells of the body, liver, adipocytes and other tissues, provide the necessary nutrients for building up the tumor, as if differentiated cells responded preferentially to catabolic signals for feeding the tumor. In fact it is slightly more complicated, since tumor cells gain such a metabolic advantage over other cells, by rewiring their metabolic pathways into a new hybrid mode, resulting from their dual sensitivity to both anabolic and catabolic signals, while differentiated cells resistant to anabolic hormones respond preferentially to catabolic ones. Stem cells committed to repair a tissue, display this dual sensitivity and become the dominant population, forming a tumor in the tissue they should have repaired. The phosphorylation of key enzymes controlling anabolic or catabolic actions is indeed compatible with this view, but where is the starter for such a process? We came to the conclusion that an alteration of GABA controls in the endocrine pancreas, would explain the metabolic rewiring observed in cancer, with the hope that an early correction with adequate compounds will prevent or heal the disease.
Résumé— L'acètylcholine a été localisée au niveau d'une fraction de vésicules synaptiques isolée à partir de l'organe électrique; le taux d'acétylcholine est fonction de la pression osmotique du milieu. La choline-acétyltransfèrase (EC 184.108.40.206) n'est pas associée à cette fraction. Les distributions sont comparées à celles de diverses enzymes.Abstract—The electric organ of Torpedo is a purely cholinergic tissue from which fractions of small vesicles 800 Å in diameter may be isolated by homogenisation and centrifugation. The vesicle fraction is rich in acetylcholine. The yield of acetylcholine in the vesicle fraction is dependent on the osmolarity of the homogenisation medium, 800 mosm being optimal. The isolated vesicles themselves lose acetylcholine when subjected to hypo-osmotic conditions. Choline acetyltransferase (EC 220.127.116.11) behaves as a cytoplasmic enzyme and is not associated with the vesicular fraction. Acetylcholinesterase (EC 18.104.22.168) is found in fractions containing membrane fragments. The cellular distribution of these components of the cholinergic synapse is similar in Torpedo electric organ and mammalian cortex.
An overview of cancer metabolism is briefly presented. Apparently, differentiated tissues resistant to insulin but sensitive to catabolic hormones become nutritional reservoirs for populations of stem cells that display at the enzymatic level a hybrid response to both insulin and glucagon. This leads them to rewire their metabolic pathways into a " carcinogenic mode " , giving them a selective advantage favoring their mitotic development. Normally, when pancreatic beta cells release insulin they co-release GABA that turns off glucagon release from alpha cells, but also terminates the release of insulin by closing its release mechanism. Hence, a GABA deficiency will induce a chronic insulin release that renders differentiated cells resistant to anabolic insulin, while sensitive to glucagon. In contrast, new mitotic stem cells that have not been submitted to desensitization, display a dual sensitivity to insulin and glucagon, no longer blocked by the release of GABA. In these stem cells glycolysis increases via insulin effects, but pyruvate kinase and pyruvate dehydrogenase are inhibited via glucagon action. This " bottle neck " at the last step of glycolysis will be overcome by a rewiring of metabolic pathways. The GABA deficiency also increases epinephrine release that blocks somatostatin release from delta cells, enhancing the effect of growth hormone on lipolysis and diacylglycerol production. The latter stimulates protein kinase C, and the formation of a phosphatase inhibitor, which maintains the glycolytic " bottle neck " and a metabolic rewiring typical of cancer.
The goal was to show that in addition to genetic factors, some common alterations of biochemical pathways are starters for both cancer and Alzheimer's disease. However, the pathways involved take different directions while the pathology develops. Understanding such mechanisms that lead to the observed lesions, may provide new possibilities for preventing or treating these plagues.
We recently proposed that deficient cellular interactions in endocrine pancreas were a primary cause for cancer. Normally, insulin secreting beta cells release in parallel GABA, for inhibiting neighboring alpha and delta cells, releasing glucagon and somatostatin respectively. A deficiency of GABA release, will lead to a hybrid anaboliccatabolic metabolism, mediated by insulin and glucagon. They act via kinases and phosphatases, on enzymatic switches rewiring metabolism, this gives to mitotic cells a selective advantage, leading them to cancer. The pancreatic GABA starter hypothesis for cancer seems verified, on human populations consuming regularly palm tree betel nuts that contain classical GABA inhibitors; epidemiological studies showed an elevated cancer risk. Since vitamin B6 is the cofactor of glutamatedecarboxylase, GABA synthesis should decrease in processes deactivating vitamin B6, and increase cancer risk. Gyromitrin a hydrazine found in a mushroom (Gyromitra esculenta) forms vitamin B6-hydrazones de-activating the vitamin; gyrometrin was clearly carcinogenic for rodents fed with uncooked gyromitra. Pathologies de-activating vitamin B6 include Pellagra, a niacin deficiency due to maize diets. In this case, amines-vitamin B6 adducts would increase cancer risk as recently suspected. Another adduct of vitamin B6, is a B6-pyrrole identified in Prolinemia. Thus, pyrroles formed by the catabolism of pyrrolizidines alkaloids, found in boraginaceae and other plant families, will de-activate vitamin B6, explaining the carcinogenicity of pyrrolizidines. In addition, vitamin B6 supplementation seems to prevent cancer. A chronic GABA A receptor inhibition by pesticides was also carcinogenic. A pancreatic GABA deficiency in endocrine pancreas might then be a starter for cancer.
1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases. 2- Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas. Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases. 3- Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis. 4- The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase) 5- IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability. 6- An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...
Tumor cells display hybrid metabolic features: some of their enzymes are phosphorylated as normally observed when catabolic hormones stimulate Gs-coupled receptors, whereas other enzymes adopt a configuration normally found in anabolic situations, mediated via tyrosine kinase receptors. Consequently, tumor cells have to rewire their metabolic pathways differently, whereas differentiated cells seem to respond preferentially to catabolic hormones. This gives mitotic cells a selective advantage since they deplete other cell reserves for their benefit. The pancreatic gamma aminobutyric acid selection switch between anabolism and catabolism explains the process, that is, a deficient release of gamma aminobutyric acid from beta cells leads to a concomitant release of catabolic glucagon and anabolic insulin and to a progressive desensitisation of insulin receptors on differentiated cells. New stem cells, with non-desensitised insulin receptors, respond to the dual anabolic and catabolic signals and rewire their metabolism in cancer mode. The aim of this letter was to discuss the causal pancreatic alteration of the anabolic-catabolic selection switch.