Cancer Causes Control (2014) 25:1733–1736 DOI 10.1007/s10552-014-0477-0
LETTER TO THE EDITOR
An alteration of the endocrine pancreas involved in cancer Maurice Israe¨l
Received: 26 July 2014 / Accepted: 7 October 2014 / Published online: 25 October 2014 Ó Springer International Publishing Switzerland 2014
Abstract 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 nondesensitised 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. Keywords Cancer metabolism Anabolic–catabolic rewiring Endocrine pancreas alteration Insulin-glucagon regulation To the editor The aim of the present letter was to give an overview on cancer metabolism that was described in detail at the
M. Israe¨l 2 av.Aristide Briand, 91440 Bures sur Yvette, France M. Israe¨l (&) CNRS, 91190 Gif surYvette, France e-mail: [email protected]
signaling level and at the enzymatic level in specialized journals. The easiest way to describe cancer metabolism for a broader less specialized audience, is to compare cancer metabolism to other classical metabolic situations observed in starvation for example or following a meal rich in carbohydrates. From such a comparison, one may identify the control mechanisms that have changed in cancer and explain the necessary metabolic rewiring observed in cancer. In addition, the elevated incidence of cancer associated with given metabolic or nutritional conditions, in relation to diabetes type 2 for example, could be clarified. The mobilization of tissue reserves in starvation is a known physiological situation; catabolic hormones, glucagon and epinephrine, act on Gs-coupled receptors increasing cAMP, which activates protein kinases (PKA/ Src) that elicit the phosphorylation of downstream enzymes supporting the production of glucose by glycogenolysis and gluconeogenesis, while other activated enzymes, mobilize fatty acids forming ketone bodies, the other cell nutrients. A typical feature of catabolic hormonal action is a phosphorylation of pyruvate kinase (PK) and pyruvate dehydrogenase (PDH) that inhibits these enzymes, closing the entry of the Krebs cycle, which spares oxaloacetate (OAA) at the start of the glucose synthesis pathway, and acetyl CoA, which forms ketone bodies. We recall that cAMP inhibits the synthesis of fructose 2-6 bisphosphate the activator of glycolysis, the direction of the pathway is then reversed from glycolysis to glucose synthesis. It can be assumed that in cancer, the loss of weight, associated with the mobilization of reserves depends of catabolic hormones, as it is the case for starvation, but in this context, there are two cases to distinguish. Indeed, the liver and the muscle do not respond in the same way to
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catabolic hormones. The muscle can as the liver, consume glycogen reserves, but unlike liver, there is a few, if any, gluconeogenesis in muscle. The reason for this is that muscles preserve glycolysis, for keeping the production of mechanical energy, which is useful if it is necessary to flee for example. This muscular exception restores glycolysis and cancels the phosphorylations that inhibited PK and PDH. It is probably an increase in muscle calcium during activity that stimulates dephosphorylating phosphatases for PK and PDH. Calcium also activates a phosphodiesterase that hydrolyzes cAMP, which restores the formation of fructose 2-6 bis phosphate, supporting in this way the glycolytic direction. If we compare to the tumor cell; the catabolic hormones block as for the liver, PK and PDH by phosphorylation, as should be in gluconeogenesis; but unlike the liver, tumor cells will restore glycolysis and reverse the metabolic flow, as occurs in muscle. This is presumably due to the activation of a phosphodiesterase that hydrolyzes the cAMP, which elicits an increase of fructose 2-6 bis phosphate, the activator of glycolysis. But unlike muscle, tumor cells are unable to dephosphorylate PK and PDH at the entrance of the Krebs cycle. If we reason from the muscle, one could tell that tumor cells activate a phosphodiesterase hydrolyzing cAMP, but fail to activate phosphatases that would dephosphorylate PK and PDH. Tumor cells will consequently have to rewire the entry of the Krebs cycle; they depend for the citrate condensation step of acetyl CoA coming essentially from liver ketone bodies. In a crucial work, on tumor cells, it is precisely the enzyme PDH, which was reactivated by dephosphorylation, using its kinase inhibitor (dichloroacetate), this led to an arrest of mitosis and apoptosis of colorectal tumor cells [1]. This observation indicates that it may be useful to act as well, on other tumor cell enzymes that change in parallel to PDH, such as PK since this has led to a ‘‘rewiring of metabolic pathways’’ that is specific for tumor cells. Opposite to starvation, a meal with increased glycaemia, elicits the release of insulin and other anabolic hormones. The action of insulin is mediated by tyrosine kinase receptors, via PKB, controlling glycolysis, while MAP kinase and PI3 kinase signaling routes are stimulated, controlling mitosis and cell survival. A parallel activation of a phospholipase generates inositol 3 Phosphate (IP3) and diacyl glycerol (DAG). Calcium release from internal stores is elicited by IP3, while DAG activates PKC. In anabolism, glycolytic metabolism takes over, oriented by the increase of its fructose 2-6 bis phosphate activator, which increases since cAMP is decreased, hydrolyzed by a phosphodiesterase activated by calcium. Protein and lipid synthesis are boosted; new molecular building blocks are formed for dividing cells.
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Cancer Causes Control (2014) 25:1733–1736
Similarly to stem cells, subjected to anabolic actions mediated by the activation of tyrosine kinase receptors, tumor cells, will incorporate glucose, display a high glycolysis and form new molecular building blocks for new mitotic daughter cells. However, unlike normal cells, tumor cells must overcome the blockade of PDH and a PK that remain phosphorylated as for catabolic effects. We are somehow in a hybrid situation for tumor cells: the response is catabolic for these two enzymes, while others enzymes are normally dephosphorylated as occurs in anabolism. Schematically, in the tumorigenic condition, enzymes such as pyruvate (PDH) and (PK) are phosphorylated and inhibited as observed for catabolism and gluconeogenesis, while other enzymes (glycogen synthase or glycogen phosphorylase for example) are dephosphorylated, in their anabolic configuration, associated with glycolysis. This hybrid situation rewires metabolic pathways in tumor cells and gives them a metabolic advantage, enabling them to plunder tissue reserves mobilized by catabolic hormones [2, 3]. How do we explain this very particular situation?
The pancreatic selection switch turns off catabolism when anabolism operates Normally, pancreatic beta cells secrete in parallel to insulin, the transmitter GABA, which switches off neighboring alpha and delta cells hyperpolarized via GABA A receptors; this inhibits the release of glucagon from alpha cells and somatostatin from delta cells. In this way, when anabolic insulin is released, catabolic glucagon is switched off by GABA [4]. Since we observe a hybrid metabolic response in tumor cells with some enzymes in their catabolic phosphorylated condition and others in their anabolic dephosphorylated configuration, it is logic to incriminate the pancreatic selection switch between anabolic and catabolic actions for explaining the anomaly. A failure of this GABA-mediated mechanism probably explains the hybrid catabolic/anabolic status of tumor cell enzymes; however, we also have to consider that in cancer, differentiated cells respond preferentially to catabolic hormones; this will be discussed in this letter. What would be the consequences of a failure of this GABA-dependent regulation of the endocrine pancreas? It may occur if glutamate decarboxylase (GAD) the GABAsynthetizing enzyme is inhibited by pesticides for example. The consummation of Betel nuts (the second worldwide addiction after tobacco) is known to inhibit GABAergic processes, via nipecotic acid and greatly favors cancer. We also suspect that vitamin B6 deficiencies affect GABA synthesis, since B6 is the cofactor of GAD. Such deficiencies might be provoked by compounds forming adducts with vitamin B6 aldehyde (hydrazines, amines, pyrroles).
Cancer Causes Control (2014) 25:1733–1736
Finally, autoimmune diseases affecting GAD have been described; it is the case for a diabetes type 1, stiff person syndrome, or paraneoplastic cerebellar degeneration. In this type 1 diabetes, beta cells are usually lysed, but weaker antibody might simply decrease GABA synthesis. In the two other diseases, heavy neurological symptoms are frequently associated with tumors. In addition, it seems that calcium dependent chloride channels (bestrophins) can release GABA they deserve to be studied in the pancreas. All these possible causes that decrease the effect of GABA synthesis or its release from beta cells would alter the switch off mechanism for glucagon that will then be released, together with insulin. A hybrid catabolic/anabolic message would be sent to cells, and indeed, tumor cells display a dual hybrid response. This is shown by the blockade of PK and PDH as for catabolism, paradoxically associated with a very active glycolysis and citrate condensation, feeding synthetic processes as for anabolism. To overcome the PK and PDH blockade, tumor cells rewire the system, they use for their citrate condensation, acetyl CoA coming from ketone bodies provided by tissue reserves, while OAA is formed via phosphoenolpyruvate carboxykinase or malate dehydrogenase. Below the citrate condensation, a new stop in the Krebs cycle favors the citrate efflux from mitochondria, which feeds via ATP citrate lyase and acetyl CoA carboxylase the synthesis of fatty acids and lipid membranes for mitotic cells. The malonyl CoA intermediate is a known inhibitor of fatty acids transport and beta oxidation in mitochondria, rendering tumor cell dependent of ketone bodies and lysolipids provided by other tissue reserves [5]. Why then enzymes of differentiated cells, hepatocytes or adipocytes, respond preferentially to catabolic hormones; as if, in cancer, differentiated cells, were relatively insensitive to insulin signals. In a way, this resembles to a situation found in diabetes type 2, in which there is a desensitization of insulin receptors, interiorized by endocytosis before proteolysis. Insulin resistance is often associated with chronic inflammation; in diabetes type 2, there is indeed an elevated cancer risk [6]. For avoiding the insulin desensitization process, beta cells normally turn off insulin release, terminating its action. In this case, the released GABA acts on metabotropic GABA B receptors of beta cells that are coupled to Gi proteins. This closes after several steps the insulin release mechanism [7] see also [8]. Hence, GABA release from beta cells functions as an autocrine inhibitor, turning off insulin release. If GABA release gets deficient, there will then be a persistent release of insulin, which desensitizes insulin receptors on differentiated cells that will respond preferentially to catabolic hormones. In mitotic cells, the situation is very different, since they respond to both insulin and glucagon, adopting a hybrid anabolic/catabolic rewiring. The simplest explanation is
1735
that in contrast to differentiated cells chronically, submitted to insulin receptor desensitization; new stem cells express new insulin receptors that have not been desensitized. And since these cells have also Gs-coupled receptors, they will display the dual anabolic/catabolic response and start the rewiring process. Moreover, if there is a general deficit of GABA, also affecting the adrenal medulla, a decreased GABA release stimulates epinephrine release, which inhibits somatostatin, favoring growth hormone-IGF actions. Glucagon also stimulates cortisol release, eliciting the proteolysis of muscle protein.
A crucial question to consider is how a systemic alteration of the endocrine pancreas elicits tumors in other organs? An aggression of organs breast liver or other, by external agents or internal toxins could be a starting point, often associated with inflammation. The lysis of cells releases in the blood stream sugars and many cellular compounds that are then sensed by the endocrine pancreas as an intake of food. This will elicit the release of anabolic insulin and IGF that stimulate the mitosis of stem cells, starting a repair of the lysed tissue. If the pancreatic GABA selection switch between anabolism and catabolism is altered, there will be a concomitant release of catabolic glucagon and anabolic insulin; moreover, the decrease of GABA will fail to terminate the release of insulin. Differentiated cells will then become relatively insensitive to insulin as occurs in diabetes type 2 and will essentially respond to catabolic signals mobilizing body stores. Stem cells that express new, not desensitized, insulin receptors receive a dual anabolic– catabolic signal and rewire their metabolic pathways in the hybrid mode that was described. They gain in this way a selective advantage over the other cells in the organ since they can plunder body stores and continue to divide. In the long run, mutations stabilize their metabolic advantage selecting the most aggressive population. The pancreatic alteration has given to these stem cells committed to repair an organ, a selective advantage that leads to a tumor in the organ they should have repaired.
Conclusion We know that diabetes type I may result from anti GAD antibodies that destroy beta cells. A survival of beta cells with an altered GABAergic control system may eventually take place. A variety of other conditions may alter as well this essential pancreatic control. This will profoundly and chronically alter metabolism. In such conditions, cells committed to repair any injury in any organ, will rewire
123
1736
Cancer Causes Control (2014) 25:1733–1736
their metabolic pathways because they receive hybrid signals, and gain a selective metabolic advantage over differentiated cells that respond preferentially to catabolic signals since their insulin receptors are desensitized by the persistent insulin release. This selective process opens their way to cancer. If detected, a correction of the pancreatic anomaly should prevent cancer. Reversing the metabolic rewiring that is its expected consequence should also heal. Of course, cancer is a multifactorial disease; however, a deficiency of the endocrine pancreas altering its GABAergic controls explains the metabolic features associated with the tumorigenic process. Conflict of interest
The author declares no conflict of interest
References 1. Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer. 102:1746–1752
123
2. Israe¨l M (2012) A primary cause of cancer: GABA deficiency in endocrine pancreas. Cancer Therapy. 8:171–183 3. Israe¨l M, Schwartz L (2011) The metabolic advantage of tumor cells. Molecular Cancer. 10(70):1–12 4. Israe¨l M (2012) A possible primary cause of cancer: deficient cellular interactions in endocrine pancreas. Molecular Cancer. 11:63–68 5. Israe¨l M (2014) Signaling and metabolism in cancer: endocrine pancreas deficiency and hybrid anabolism–catabolism, drugs that undo the process. Cancer Therapy. 10:1–12 6. Hemminki K, Li X, Sundquist J, Sundquist K (2010) Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 15(6):548–555 7. Braun M, Wendt A, Buchard K, Salehi A, Sewing S, Gromada J, Rorsman P (2004) GABAB receptor activation inhibits exocytosis in rat pancreatic-b-cells by G-protein-dependent activation of calcineurin. J. Pysiol. 559(Pt2):397–409 8. Taneera J, Jin Z, Jin Y, Muhammed SJ, Zhang E, Lang S, Korsgren O, Renstro¨m E, Groop L, Birnir B (2012) c-Aminobutyric acid (GABA) signaling in human pancreatic islets is altered in type 2 diabetes. Diabetologia. 55(7):1985–1994
LETTER TO THE EDITOR
An alteration of the endocrine pancreas involved in cancer Maurice Israe¨l
Received: 26 July 2014 / Accepted: 7 October 2014 / Published online: 25 October 2014 Ó Springer International Publishing Switzerland 2014
Abstract 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 nondesensitised 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. Keywords Cancer metabolism Anabolic–catabolic rewiring Endocrine pancreas alteration Insulin-glucagon regulation To the editor The aim of the present letter was to give an overview on cancer metabolism that was described in detail at the
M. Israe¨l 2 av.Aristide Briand, 91440 Bures sur Yvette, France M. Israe¨l (&) CNRS, 91190 Gif surYvette, France e-mail: [email protected]
signaling level and at the enzymatic level in specialized journals. The easiest way to describe cancer metabolism for a broader less specialized audience, is to compare cancer metabolism to other classical metabolic situations observed in starvation for example or following a meal rich in carbohydrates. From such a comparison, one may identify the control mechanisms that have changed in cancer and explain the necessary metabolic rewiring observed in cancer. In addition, the elevated incidence of cancer associated with given metabolic or nutritional conditions, in relation to diabetes type 2 for example, could be clarified. The mobilization of tissue reserves in starvation is a known physiological situation; catabolic hormones, glucagon and epinephrine, act on Gs-coupled receptors increasing cAMP, which activates protein kinases (PKA/ Src) that elicit the phosphorylation of downstream enzymes supporting the production of glucose by glycogenolysis and gluconeogenesis, while other activated enzymes, mobilize fatty acids forming ketone bodies, the other cell nutrients. A typical feature of catabolic hormonal action is a phosphorylation of pyruvate kinase (PK) and pyruvate dehydrogenase (PDH) that inhibits these enzymes, closing the entry of the Krebs cycle, which spares oxaloacetate (OAA) at the start of the glucose synthesis pathway, and acetyl CoA, which forms ketone bodies. We recall that cAMP inhibits the synthesis of fructose 2-6 bisphosphate the activator of glycolysis, the direction of the pathway is then reversed from glycolysis to glucose synthesis. It can be assumed that in cancer, the loss of weight, associated with the mobilization of reserves depends of catabolic hormones, as it is the case for starvation, but in this context, there are two cases to distinguish. Indeed, the liver and the muscle do not respond in the same way to
123
1734
catabolic hormones. The muscle can as the liver, consume glycogen reserves, but unlike liver, there is a few, if any, gluconeogenesis in muscle. The reason for this is that muscles preserve glycolysis, for keeping the production of mechanical energy, which is useful if it is necessary to flee for example. This muscular exception restores glycolysis and cancels the phosphorylations that inhibited PK and PDH. It is probably an increase in muscle calcium during activity that stimulates dephosphorylating phosphatases for PK and PDH. Calcium also activates a phosphodiesterase that hydrolyzes cAMP, which restores the formation of fructose 2-6 bis phosphate, supporting in this way the glycolytic direction. If we compare to the tumor cell; the catabolic hormones block as for the liver, PK and PDH by phosphorylation, as should be in gluconeogenesis; but unlike the liver, tumor cells will restore glycolysis and reverse the metabolic flow, as occurs in muscle. This is presumably due to the activation of a phosphodiesterase that hydrolyzes the cAMP, which elicits an increase of fructose 2-6 bis phosphate, the activator of glycolysis. But unlike muscle, tumor cells are unable to dephosphorylate PK and PDH at the entrance of the Krebs cycle. If we reason from the muscle, one could tell that tumor cells activate a phosphodiesterase hydrolyzing cAMP, but fail to activate phosphatases that would dephosphorylate PK and PDH. Tumor cells will consequently have to rewire the entry of the Krebs cycle; they depend for the citrate condensation step of acetyl CoA coming essentially from liver ketone bodies. In a crucial work, on tumor cells, it is precisely the enzyme PDH, which was reactivated by dephosphorylation, using its kinase inhibitor (dichloroacetate), this led to an arrest of mitosis and apoptosis of colorectal tumor cells [1]. This observation indicates that it may be useful to act as well, on other tumor cell enzymes that change in parallel to PDH, such as PK since this has led to a ‘‘rewiring of metabolic pathways’’ that is specific for tumor cells. Opposite to starvation, a meal with increased glycaemia, elicits the release of insulin and other anabolic hormones. The action of insulin is mediated by tyrosine kinase receptors, via PKB, controlling glycolysis, while MAP kinase and PI3 kinase signaling routes are stimulated, controlling mitosis and cell survival. A parallel activation of a phospholipase generates inositol 3 Phosphate (IP3) and diacyl glycerol (DAG). Calcium release from internal stores is elicited by IP3, while DAG activates PKC. In anabolism, glycolytic metabolism takes over, oriented by the increase of its fructose 2-6 bis phosphate activator, which increases since cAMP is decreased, hydrolyzed by a phosphodiesterase activated by calcium. Protein and lipid synthesis are boosted; new molecular building blocks are formed for dividing cells.
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Cancer Causes Control (2014) 25:1733–1736
Similarly to stem cells, subjected to anabolic actions mediated by the activation of tyrosine kinase receptors, tumor cells, will incorporate glucose, display a high glycolysis and form new molecular building blocks for new mitotic daughter cells. However, unlike normal cells, tumor cells must overcome the blockade of PDH and a PK that remain phosphorylated as for catabolic effects. We are somehow in a hybrid situation for tumor cells: the response is catabolic for these two enzymes, while others enzymes are normally dephosphorylated as occurs in anabolism. Schematically, in the tumorigenic condition, enzymes such as pyruvate (PDH) and (PK) are phosphorylated and inhibited as observed for catabolism and gluconeogenesis, while other enzymes (glycogen synthase or glycogen phosphorylase for example) are dephosphorylated, in their anabolic configuration, associated with glycolysis. This hybrid situation rewires metabolic pathways in tumor cells and gives them a metabolic advantage, enabling them to plunder tissue reserves mobilized by catabolic hormones [2, 3]. How do we explain this very particular situation?
The pancreatic selection switch turns off catabolism when anabolism operates Normally, pancreatic beta cells secrete in parallel to insulin, the transmitter GABA, which switches off neighboring alpha and delta cells hyperpolarized via GABA A receptors; this inhibits the release of glucagon from alpha cells and somatostatin from delta cells. In this way, when anabolic insulin is released, catabolic glucagon is switched off by GABA [4]. Since we observe a hybrid metabolic response in tumor cells with some enzymes in their catabolic phosphorylated condition and others in their anabolic dephosphorylated configuration, it is logic to incriminate the pancreatic selection switch between anabolic and catabolic actions for explaining the anomaly. A failure of this GABA-mediated mechanism probably explains the hybrid catabolic/anabolic status of tumor cell enzymes; however, we also have to consider that in cancer, differentiated cells respond preferentially to catabolic hormones; this will be discussed in this letter. What would be the consequences of a failure of this GABA-dependent regulation of the endocrine pancreas? It may occur if glutamate decarboxylase (GAD) the GABAsynthetizing enzyme is inhibited by pesticides for example. The consummation of Betel nuts (the second worldwide addiction after tobacco) is known to inhibit GABAergic processes, via nipecotic acid and greatly favors cancer. We also suspect that vitamin B6 deficiencies affect GABA synthesis, since B6 is the cofactor of GAD. Such deficiencies might be provoked by compounds forming adducts with vitamin B6 aldehyde (hydrazines, amines, pyrroles).
Cancer Causes Control (2014) 25:1733–1736
Finally, autoimmune diseases affecting GAD have been described; it is the case for a diabetes type 1, stiff person syndrome, or paraneoplastic cerebellar degeneration. In this type 1 diabetes, beta cells are usually lysed, but weaker antibody might simply decrease GABA synthesis. In the two other diseases, heavy neurological symptoms are frequently associated with tumors. In addition, it seems that calcium dependent chloride channels (bestrophins) can release GABA they deserve to be studied in the pancreas. All these possible causes that decrease the effect of GABA synthesis or its release from beta cells would alter the switch off mechanism for glucagon that will then be released, together with insulin. A hybrid catabolic/anabolic message would be sent to cells, and indeed, tumor cells display a dual hybrid response. This is shown by the blockade of PK and PDH as for catabolism, paradoxically associated with a very active glycolysis and citrate condensation, feeding synthetic processes as for anabolism. To overcome the PK and PDH blockade, tumor cells rewire the system, they use for their citrate condensation, acetyl CoA coming from ketone bodies provided by tissue reserves, while OAA is formed via phosphoenolpyruvate carboxykinase or malate dehydrogenase. Below the citrate condensation, a new stop in the Krebs cycle favors the citrate efflux from mitochondria, which feeds via ATP citrate lyase and acetyl CoA carboxylase the synthesis of fatty acids and lipid membranes for mitotic cells. The malonyl CoA intermediate is a known inhibitor of fatty acids transport and beta oxidation in mitochondria, rendering tumor cell dependent of ketone bodies and lysolipids provided by other tissue reserves [5]. Why then enzymes of differentiated cells, hepatocytes or adipocytes, respond preferentially to catabolic hormones; as if, in cancer, differentiated cells, were relatively insensitive to insulin signals. In a way, this resembles to a situation found in diabetes type 2, in which there is a desensitization of insulin receptors, interiorized by endocytosis before proteolysis. Insulin resistance is often associated with chronic inflammation; in diabetes type 2, there is indeed an elevated cancer risk [6]. For avoiding the insulin desensitization process, beta cells normally turn off insulin release, terminating its action. In this case, the released GABA acts on metabotropic GABA B receptors of beta cells that are coupled to Gi proteins. This closes after several steps the insulin release mechanism [7] see also [8]. Hence, GABA release from beta cells functions as an autocrine inhibitor, turning off insulin release. If GABA release gets deficient, there will then be a persistent release of insulin, which desensitizes insulin receptors on differentiated cells that will respond preferentially to catabolic hormones. In mitotic cells, the situation is very different, since they respond to both insulin and glucagon, adopting a hybrid anabolic/catabolic rewiring. The simplest explanation is
1735
that in contrast to differentiated cells chronically, submitted to insulin receptor desensitization; new stem cells express new insulin receptors that have not been desensitized. And since these cells have also Gs-coupled receptors, they will display the dual anabolic/catabolic response and start the rewiring process. Moreover, if there is a general deficit of GABA, also affecting the adrenal medulla, a decreased GABA release stimulates epinephrine release, which inhibits somatostatin, favoring growth hormone-IGF actions. Glucagon also stimulates cortisol release, eliciting the proteolysis of muscle protein.
A crucial question to consider is how a systemic alteration of the endocrine pancreas elicits tumors in other organs? An aggression of organs breast liver or other, by external agents or internal toxins could be a starting point, often associated with inflammation. The lysis of cells releases in the blood stream sugars and many cellular compounds that are then sensed by the endocrine pancreas as an intake of food. This will elicit the release of anabolic insulin and IGF that stimulate the mitosis of stem cells, starting a repair of the lysed tissue. If the pancreatic GABA selection switch between anabolism and catabolism is altered, there will be a concomitant release of catabolic glucagon and anabolic insulin; moreover, the decrease of GABA will fail to terminate the release of insulin. Differentiated cells will then become relatively insensitive to insulin as occurs in diabetes type 2 and will essentially respond to catabolic signals mobilizing body stores. Stem cells that express new, not desensitized, insulin receptors receive a dual anabolic– catabolic signal and rewire their metabolic pathways in the hybrid mode that was described. They gain in this way a selective advantage over the other cells in the organ since they can plunder body stores and continue to divide. In the long run, mutations stabilize their metabolic advantage selecting the most aggressive population. The pancreatic alteration has given to these stem cells committed to repair an organ, a selective advantage that leads to a tumor in the organ they should have repaired.
Conclusion We know that diabetes type I may result from anti GAD antibodies that destroy beta cells. A survival of beta cells with an altered GABAergic control system may eventually take place. A variety of other conditions may alter as well this essential pancreatic control. This will profoundly and chronically alter metabolism. In such conditions, cells committed to repair any injury in any organ, will rewire
123
1736
Cancer Causes Control (2014) 25:1733–1736
their metabolic pathways because they receive hybrid signals, and gain a selective metabolic advantage over differentiated cells that respond preferentially to catabolic signals since their insulin receptors are desensitized by the persistent insulin release. This selective process opens their way to cancer. If detected, a correction of the pancreatic anomaly should prevent cancer. Reversing the metabolic rewiring that is its expected consequence should also heal. Of course, cancer is a multifactorial disease; however, a deficiency of the endocrine pancreas altering its GABAergic controls explains the metabolic features associated with the tumorigenic process. Conflict of interest
The author declares no conflict of interest
References 1. Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer. 102:1746–1752
123
2. Israe¨l M (2012) A primary cause of cancer: GABA deficiency in endocrine pancreas. Cancer Therapy. 8:171–183 3. Israe¨l M, Schwartz L (2011) The metabolic advantage of tumor cells. Molecular Cancer. 10(70):1–12 4. Israe¨l M (2012) A possible primary cause of cancer: deficient cellular interactions in endocrine pancreas. Molecular Cancer. 11:63–68 5. Israe¨l M (2014) Signaling and metabolism in cancer: endocrine pancreas deficiency and hybrid anabolism–catabolism, drugs that undo the process. Cancer Therapy. 10:1–12 6. Hemminki K, Li X, Sundquist J, Sundquist K (2010) Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 15(6):548–555 7. Braun M, Wendt A, Buchard K, Salehi A, Sewing S, Gromada J, Rorsman P (2004) GABAB receptor activation inhibits exocytosis in rat pancreatic-b-cells by G-protein-dependent activation of calcineurin. J. Pysiol. 559(Pt2):397–409 8. Taneera J, Jin Z, Jin Y, Muhammed SJ, Zhang E, Lang S, Korsgren O, Renstro¨m E, Groop L, Birnir B (2012) c-Aminobutyric acid (GABA) signaling in human pancreatic islets is altered in type 2 diabetes. Diabetologia. 55(7):1985–1994
