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Targeting AMPK for cancer prevention and treatment.

Li W, Saud SM, Young MR, Chen G, Hua B - Oncotarget (2015)

Bottom Line: AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis.AMPK is activated in response to a shortage of energy.Once activated, AMPK can promote ATP production and regulate metabolic energy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

ABSTRACT
AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism.

No MeSH data available.


Related in: MedlinePlus

AMPK is a tumor suppressor for cancer prevention and treatmentNSAIDs, Natural products, TCM and metformin can all activate AMPK. AMPK negatively regulates the mTOR signal pathway, resulting in inhibition of cancer proliferation and growth. Activated AMPK negatively regulates COX-2, a pro-inflammatory enzyme associated with tumorigenesis. AMPK can induce phosphorylation of tumor suppressor p53, resulting in cell cycle arrest. Activation of AMPK can also induce phosphorylation of ACC influencing lipid metabolism. Interactions leading to activation of molecular targets are indicated by arrows; those inhibited are indicated by a bar. Activation of AMPK can modulate multiple pathways leading to anticancer activities. TCM=Traditional Chinese Medicine; NSAIDs=Non-steroidal anti-inflammatory drugs.
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Figure 1: AMPK is a tumor suppressor for cancer prevention and treatmentNSAIDs, Natural products, TCM and metformin can all activate AMPK. AMPK negatively regulates the mTOR signal pathway, resulting in inhibition of cancer proliferation and growth. Activated AMPK negatively regulates COX-2, a pro-inflammatory enzyme associated with tumorigenesis. AMPK can induce phosphorylation of tumor suppressor p53, resulting in cell cycle arrest. Activation of AMPK can also induce phosphorylation of ACC influencing lipid metabolism. Interactions leading to activation of molecular targets are indicated by arrows; those inhibited are indicated by a bar. Activation of AMPK can modulate multiple pathways leading to anticancer activities. TCM=Traditional Chinese Medicine; NSAIDs=Non-steroidal anti-inflammatory drugs.

Mentions: The use of natural products as chemopreventive agents has increased worldwide because of their potential low toxicity and effectiveness [118]. Observational studies have suggested the efficacy of some natural products in preventing the development of cancer; however, clinical trials have yet to be conducted in most cases to support this notion. In preclinical studies, several classes of natural products have been shown to target many mediators that play important roles in cancer, including AMPK (Figure 1 and Table 1). Flavones, such as wogonin [119], tanshinone IIA [120], quercetin [121, 122] and cryptotanshinone [123] induce AMPK activation inhibiting proliferation and inducing apoptosis in various types of cancer cells. Polyphenols are also an abundant source of AMPK activators. Resveratrol induces autophagy in chronic myelogenous leukemia cells by regulating the AMPK/mTOR pathway [124]. In colorectal cancer cells, magnolol [125], epigallocatechin-3-gallate (EGCG) [126], and widdrol [127] could induce apoptosis, inhibit migration, and prevent invasion by AMPK-dependent mechanisms. In breast cancer cells, nordihydroguaiaretic acid inhibits mTORC1 activity through disruption of mTOR-Raptor complex and AMPK activation [128], while demethoxycurcumin, a potent AMPK activator has broad spectrum anticancer activity in triple-negative breast cancer cells [129] with the parent compound curcumin exerting similar effects in ovarian cancer cells [130] and in colorectal cancer cells by AMPK-p53 activation [131, 132]. Antroquinonol, extracted from antrodiacamphorate displays anti-cancer activity against HCC cells through an AMPK-dependent manner [133] and honokiol, has been shown to inhibit proliferation in several cancer cell types, also through AMPK dependent mechanisms [134]. Berberine has been shown to inhibit colon tumor formation in AOM/DSS mouse model through activation of AMPK [135]. Berberine [11]or Ginsenoside 20-O-b-D-Glucopyranosyl-20(S)-Protopanaxadiol [48] inhibit melanoma cell growth and invasion through the activation of AMPK in vitro [11, 48-52]. Thus, these agents may serve as AMPK activators and provide a crucial link between natural products and the prevention and treatment of cancer.


Targeting AMPK for cancer prevention and treatment.

Li W, Saud SM, Young MR, Chen G, Hua B - Oncotarget (2015)

AMPK is a tumor suppressor for cancer prevention and treatmentNSAIDs, Natural products, TCM and metformin can all activate AMPK. AMPK negatively regulates the mTOR signal pathway, resulting in inhibition of cancer proliferation and growth. Activated AMPK negatively regulates COX-2, a pro-inflammatory enzyme associated with tumorigenesis. AMPK can induce phosphorylation of tumor suppressor p53, resulting in cell cycle arrest. Activation of AMPK can also induce phosphorylation of ACC influencing lipid metabolism. Interactions leading to activation of molecular targets are indicated by arrows; those inhibited are indicated by a bar. Activation of AMPK can modulate multiple pathways leading to anticancer activities. TCM=Traditional Chinese Medicine; NSAIDs=Non-steroidal anti-inflammatory drugs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480686&req=5

Figure 1: AMPK is a tumor suppressor for cancer prevention and treatmentNSAIDs, Natural products, TCM and metformin can all activate AMPK. AMPK negatively regulates the mTOR signal pathway, resulting in inhibition of cancer proliferation and growth. Activated AMPK negatively regulates COX-2, a pro-inflammatory enzyme associated with tumorigenesis. AMPK can induce phosphorylation of tumor suppressor p53, resulting in cell cycle arrest. Activation of AMPK can also induce phosphorylation of ACC influencing lipid metabolism. Interactions leading to activation of molecular targets are indicated by arrows; those inhibited are indicated by a bar. Activation of AMPK can modulate multiple pathways leading to anticancer activities. TCM=Traditional Chinese Medicine; NSAIDs=Non-steroidal anti-inflammatory drugs.
Mentions: The use of natural products as chemopreventive agents has increased worldwide because of their potential low toxicity and effectiveness [118]. Observational studies have suggested the efficacy of some natural products in preventing the development of cancer; however, clinical trials have yet to be conducted in most cases to support this notion. In preclinical studies, several classes of natural products have been shown to target many mediators that play important roles in cancer, including AMPK (Figure 1 and Table 1). Flavones, such as wogonin [119], tanshinone IIA [120], quercetin [121, 122] and cryptotanshinone [123] induce AMPK activation inhibiting proliferation and inducing apoptosis in various types of cancer cells. Polyphenols are also an abundant source of AMPK activators. Resveratrol induces autophagy in chronic myelogenous leukemia cells by regulating the AMPK/mTOR pathway [124]. In colorectal cancer cells, magnolol [125], epigallocatechin-3-gallate (EGCG) [126], and widdrol [127] could induce apoptosis, inhibit migration, and prevent invasion by AMPK-dependent mechanisms. In breast cancer cells, nordihydroguaiaretic acid inhibits mTORC1 activity through disruption of mTOR-Raptor complex and AMPK activation [128], while demethoxycurcumin, a potent AMPK activator has broad spectrum anticancer activity in triple-negative breast cancer cells [129] with the parent compound curcumin exerting similar effects in ovarian cancer cells [130] and in colorectal cancer cells by AMPK-p53 activation [131, 132]. Antroquinonol, extracted from antrodiacamphorate displays anti-cancer activity against HCC cells through an AMPK-dependent manner [133] and honokiol, has been shown to inhibit proliferation in several cancer cell types, also through AMPK dependent mechanisms [134]. Berberine has been shown to inhibit colon tumor formation in AOM/DSS mouse model through activation of AMPK [135]. Berberine [11]or Ginsenoside 20-O-b-D-Glucopyranosyl-20(S)-Protopanaxadiol [48] inhibit melanoma cell growth and invasion through the activation of AMPK in vitro [11, 48-52]. Thus, these agents may serve as AMPK activators and provide a crucial link between natural products and the prevention and treatment of cancer.

Bottom Line: AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis.AMPK is activated in response to a shortage of energy.Once activated, AMPK can promote ATP production and regulate metabolic energy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

ABSTRACT
AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. AMPK is activated in response to a shortage of energy. Once activated, AMPK can promote ATP production and regulate metabolic energy. AMPK is a known target for treating metabolic syndrome and type-2 diabetes; however, recently AMPK is emerging as a possible metabolic tumor suppressor and target for cancer prevention and treatment. Recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer. In this article we review the role of AMPK in regulating inflammation, metabolism, and other regulatory processes with an emphasis on cancer, as well as, discuss the potential for targeting AMPK to treat various types of cancer. Activation of AMPK has been found to oppose tumor progression in several cancer types and offers a promising cancer therapy. This review evaluates the evidence linking AMPK with tumor suppressor function and analyzes the molecular mechanisms involved. AMPK activity opposes tumor development and progression in part by regulating inflammation and metabolism.

No MeSH data available.


Related in: MedlinePlus