AMPK As a Metabolic Tumor Suppressor: Control of Metabolism and Cell Growth

Abstract

AMPK is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for metabolic syndrome and Type 2 diabetes. Recent studies indicate that AMPK plays a role in linking metabolic syndrome and cancer. AMPK is an essential mediator of the tumor suppressor LKB1 and could be suppressed in cancer cells containing loss-of-function mutations of LKB1 or containing active mutations of B-Raf, or in cancers associated with metabolic syndrome. The activation of AMPK reprograms cellular metabolism and enforces metabolic checkpoints by acting on mTORC1, p53, fatty acid synthase and other molecules for regulating cell growth and metabolism. In keeping with in vitro studies, recent epidemiological studies indicate that the incidence of cancer is reduced in Type 2 diabetes treated with metformin, an AMPK activator. Thus, AMPK is emerging as an interesting metabolic tumor suppressor and a promising target for cancer prevention and therapy. Keywordsacetyl CoA carboxylase; AMPK; fatty acid synthase; LKB1; metabolic syndrome; metabolism; mTOR; p53; tumor suppressor; tumorigenesis AMP-activated protein kinase acts as a fuel gauge that is activated under stresses such as hypoxia, ischemia, glucose deprivation and exercise [1]. Activation of AMPK stimulates fatty †Author for correspondence: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Evans 645, Boston, MA 02118, USA, Tel.: +1 617 414 1033, Fax: +1 617 414 1646, zluo@bu.edu. For reprint orders, please contact: reprints@futuremedicine.com Financial & competing interests disclosureThis work is supported by an NIH grant (R01CA118918 to Zhijun Luo). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript acid oxidation to generate more ATP to cope with acute energy demand and inhibits anabolic processes that consume ATP [1]. As a result, energy is preserved for acute cellular programs. In addition, AMPK activation enhances insulin sensitivity, inhibits hepatic glucose production, stimulates glucose uptake in muscle, inhibits fatty acid synthesis and esterification, and diminishes proinflammatory changes [2]. Thus, AMPK is a well-accepted target for the treatment of metabolic syndrome and Type 2 diabetes (for extensive reviews, refer to [1][2][3]). During the last 5 years, since our first review [3], great attention has been drawn to link AMPK and cancer, and substantial progress has been made. AMPK, by regulating a variety o...

Autophagy Involvement in Olanzapine-Mediated Cytotoxic Effects in Human Glioma Cells

“…Although autophagy is primarily a process for the cell protection, it can also play a role in cell death (Mizushima et al, 2008). It has been shown that a number of tumor suppressors can promote autophagy, such as LKB1 (Liang et al, 2007) , TSC (Zhou et al, 2009), DAP kinase (Bialik and Kimchi, 2010), PTEN (Errafiy et al, 2013), UVRAG (ultraviolet radiation resistanceassociated gene) (Liang et al, 2006) and AMPK (Luo et al, 2010). Interestingly, autophagy in TMZ-resistant glioblastoma cells cannot be induced by TMZ while the combination of VPA and TMZ can enhance autophagic cell death in TMZ-resistant glioma cells (Ryu et al, 2012).…”

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

“…This gene was later found to be a target for mutational inactivation in human malignancies including non-small cell lung carcinoma (Sanchez-Cespedes et al, 2002;Carretero et al, 2004;Ji et al, 2007;Matsumoto et al, 2007;Makowski and Hayes, 2008;Komiya et al, 2010;Mahoney et al, 2009), cervical carcinoma (Wingo et al, 2009), melanoma (Guldberg et al, 1999;Rowan et al, 1999) and others (Sanchez-Cespedes, 2007). The LKB1 gene encodes a serine/threonine kinase essential for the activation of AMPK (AMP-activated protein kinase) and 12 AMPK-related kinases; thus, it regulates multiple signaling pathways in cell growth, cell polarity and metabolism (Hezel and Bardeesy, 2008;Shackelford and Shaw, 2009;Luo et al, 2010). Currently, information regarding the exact roles and mechanisms underlying LKB1-mediating tumor suppression remains limited.…”

Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity

“…11 In addition to these well-characterized functions in metabolic syndromes, AMPK serves as a metabolic tumor suppressor that reprograms the cellular metabolism and elicits a metabolic checkpoint on the cell cycle through its actions on mTORC1, p53, and other modulators for cell proliferation, cell growth, cell survival, and autophagy. 12 Further, LKB1 activates AMPK and represses RNA synthesis. 13 In LKB1-deficient lung cancer cells, AMPK activity is suppressed, leading to increased cell growth, whereas the ability of AMPK to inhibit cell growth is restored when wild-type LKB1 is expressed.…”