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Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA - J Cancer (2014)

Bottom Line: Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors.In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes.We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha - Qatar;

ABSTRACT
Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

No MeSH data available.


Related in: MedlinePlus

Mechanism and Role of AMPK activation. AMP-activated protein kinase (AMPK), a serine/threonine kinase, is an energy sensor whose activity is regulated by glucose. AMPK activation, secondary to a change in the AMP/ATP ratio, activation by upstream kinases, such as CAMKK (CaMK kinase) and LKB1, or administration of metformin by direct activation of LKB1, slows metabolic reactions that consume ATP and stimulates reactions that produce ATP, thereby restoring the AMP/ATP ratio and the normal cellular energy stores. AMPK activation will in turn induce catabolic pathways, such as fatty acid oxidation by inactivating acetyl CoA carboxylase (ACC2), and will inhibit anabolic pathways, such as fatty acid synthesis, mediated by ACC1. The mTOR pathway suppresses apoptosis via its effect on the tumor suppressors p53 and p27 and inhibits autophagy by suppressing UNC-51-like kinase 1 (ULK1) and ULK2. AMPK activation downregulates the tumorigenic effects of mTOR through the TSC1/TSC2 complex, thus leading to increased apoptosis and autophagy-mediated cell death. AMPK activation also inactivates P70S6K and 4E-BP1 subsequently inhibiting protein synthesis. AMPK activation regulates the transcription factor FOXO3, which in turn increases antioxidant gene expression.
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Figure 3: Mechanism and Role of AMPK activation. AMP-activated protein kinase (AMPK), a serine/threonine kinase, is an energy sensor whose activity is regulated by glucose. AMPK activation, secondary to a change in the AMP/ATP ratio, activation by upstream kinases, such as CAMKK (CaMK kinase) and LKB1, or administration of metformin by direct activation of LKB1, slows metabolic reactions that consume ATP and stimulates reactions that produce ATP, thereby restoring the AMP/ATP ratio and the normal cellular energy stores. AMPK activation will in turn induce catabolic pathways, such as fatty acid oxidation by inactivating acetyl CoA carboxylase (ACC2), and will inhibit anabolic pathways, such as fatty acid synthesis, mediated by ACC1. The mTOR pathway suppresses apoptosis via its effect on the tumor suppressors p53 and p27 and inhibits autophagy by suppressing UNC-51-like kinase 1 (ULK1) and ULK2. AMPK activation downregulates the tumorigenic effects of mTOR through the TSC1/TSC2 complex, thus leading to increased apoptosis and autophagy-mediated cell death. AMPK activation also inactivates P70S6K and 4E-BP1 subsequently inhibiting protein synthesis. AMPK activation regulates the transcription factor FOXO3, which in turn increases antioxidant gene expression.

Mentions: Multifactorial mechanisms account for metformin's therapeutic contribution to its anti-oncogenic properties. Metformin inhibits complex 1 of mitochondrial electron transport chain 27-29, and thereby attenuates oxidative respiration resulting in ATP/AMP ratio imbalance, which in turn activates liver kinase B1 (LKB1) and AMPK 29, 30. Dephosphorylation by protein phosphatase 2A (PP2A) reversibly decreases enzyme efficiency (inactivation) of AMPK. Interestingly, metformin interplay with cellular metabolic homeostasis extends to inhibition of AMP deaminase to increase the pool of AMP available for activation of AMPK 31. Thus, AMPK can choreograph a network of diverse molecular signaling routes depending on the contextual requirements for physiological cellular homeostasis and/or pathophysiological states (Fig. 3).


Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Anwar MA, Kheir WA, Eid S, Fares J, Liu X, Eid AH, Eid AA - J Cancer (2014)

Mechanism and Role of AMPK activation. AMP-activated protein kinase (AMPK), a serine/threonine kinase, is an energy sensor whose activity is regulated by glucose. AMPK activation, secondary to a change in the AMP/ATP ratio, activation by upstream kinases, such as CAMKK (CaMK kinase) and LKB1, or administration of metformin by direct activation of LKB1, slows metabolic reactions that consume ATP and stimulates reactions that produce ATP, thereby restoring the AMP/ATP ratio and the normal cellular energy stores. AMPK activation will in turn induce catabolic pathways, such as fatty acid oxidation by inactivating acetyl CoA carboxylase (ACC2), and will inhibit anabolic pathways, such as fatty acid synthesis, mediated by ACC1. The mTOR pathway suppresses apoptosis via its effect on the tumor suppressors p53 and p27 and inhibits autophagy by suppressing UNC-51-like kinase 1 (ULK1) and ULK2. AMPK activation downregulates the tumorigenic effects of mTOR through the TSC1/TSC2 complex, thus leading to increased apoptosis and autophagy-mediated cell death. AMPK activation also inactivates P70S6K and 4E-BP1 subsequently inhibiting protein synthesis. AMPK activation regulates the transcription factor FOXO3, which in turn increases antioxidant gene expression.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4216797&req=5

Figure 3: Mechanism and Role of AMPK activation. AMP-activated protein kinase (AMPK), a serine/threonine kinase, is an energy sensor whose activity is regulated by glucose. AMPK activation, secondary to a change in the AMP/ATP ratio, activation by upstream kinases, such as CAMKK (CaMK kinase) and LKB1, or administration of metformin by direct activation of LKB1, slows metabolic reactions that consume ATP and stimulates reactions that produce ATP, thereby restoring the AMP/ATP ratio and the normal cellular energy stores. AMPK activation will in turn induce catabolic pathways, such as fatty acid oxidation by inactivating acetyl CoA carboxylase (ACC2), and will inhibit anabolic pathways, such as fatty acid synthesis, mediated by ACC1. The mTOR pathway suppresses apoptosis via its effect on the tumor suppressors p53 and p27 and inhibits autophagy by suppressing UNC-51-like kinase 1 (ULK1) and ULK2. AMPK activation downregulates the tumorigenic effects of mTOR through the TSC1/TSC2 complex, thus leading to increased apoptosis and autophagy-mediated cell death. AMPK activation also inactivates P70S6K and 4E-BP1 subsequently inhibiting protein synthesis. AMPK activation regulates the transcription factor FOXO3, which in turn increases antioxidant gene expression.
Mentions: Multifactorial mechanisms account for metformin's therapeutic contribution to its anti-oncogenic properties. Metformin inhibits complex 1 of mitochondrial electron transport chain 27-29, and thereby attenuates oxidative respiration resulting in ATP/AMP ratio imbalance, which in turn activates liver kinase B1 (LKB1) and AMPK 29, 30. Dephosphorylation by protein phosphatase 2A (PP2A) reversibly decreases enzyme efficiency (inactivation) of AMPK. Interestingly, metformin interplay with cellular metabolic homeostasis extends to inhibition of AMP deaminase to increase the pool of AMP available for activation of AMPK 31. Thus, AMPK can choreograph a network of diverse molecular signaling routes depending on the contextual requirements for physiological cellular homeostasis and/or pathophysiological states (Fig. 3).

Bottom Line: Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors.In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes.We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha - Qatar;

ABSTRACT
Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

No MeSH data available.


Related in: MedlinePlus