5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors

Laderoute, Keith R.; Calaoagan, Joy M.; Chao, Wan‐Ru; Dinh, Dominic; Denko, Nicholas C.; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, László G.

doi:10.1074/jbc.m114.576371

Cited by 61 publications

(51 citation statements)

References 37 publications

(61 reference statements)

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“…A hallmark of cancer metabolic reprograming is aerobic glycolysis (Warburg effect). Several studies now show that active AMPK supports glycolysis in human tumors [116,125,156,188,189], although it countered the Warburg effect in a mouse model of lymphoma [129], reflecting a possible tumor or species-specific role of AMPK in glycolysis. Is AMPK activated or inhibited during transformation to cope with transformation-associated metabolic reprograming?…”

Section: Discussionmentioning

confidence: 99%

“…The caveat is that most of these are in vitro studies that need to be tested in vivo . A few in vivo studies that indicate that AMPK has a contrasting role in cancer includes its tumor promoting role in RAS-transformed fibroblasts, astrocytic and breast tumors [119,120,125], and its tumor suppressive role in a mouse model of Myc-induced lymphoma [129]. Recently, in vitro genetic studies also showed a growth suppressive action of AMPK through its regulation of the Hippo pathway [130–132].…”

Section: The Many Functions Of Ampkmentioning

confidence: 99%

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Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. AMPK executes numerous cellular functions, some of which are often perceived at odds with each other. While AMPK is essential for embryonic growth and development, its full impact in adult tissues is revealed under stressful situations that organisms face in the real world. Conflicting reports about its cellular functions, particularly in cancer, are intriguing and a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. Whether these drugs will have only context-specific benefits or detrimental effects in the treatment of human cancer will be a subject of intense research. Here we review the current state of AMPK research with an emphasis on cancer and discuss the yet unresolved context-dependent functions of AMPK in human cancer.

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Section: Discussionmentioning

confidence: 99%

Section: The Many Functions Of Ampkmentioning

confidence: 99%

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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“…Recent evidence showed the key role of AMPK in supporting tumor growth in aggressive breast and astrocytic tumors (46–49). Moreover, in contrast to the results obtained by Faubert et al in a lymphoma model (21), MYC has been shown to establish a dependence on AMPK-related kinase 5 (ARK5) to maintain metabolic homeostasis and cell survival.…”

Section: Role Of Ampk In Cancer: Pre-clinical Studiesmentioning

confidence: 99%

Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Zadra

Batista

Loda

2015

Molecular Cancer Research

175

162

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The precise role of 5′AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. While it is well established that activation of this energy sensor inhibits the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a “conditional” tumor suppressor and “contextual” oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation and provides an overview of the most relevant data available on AMPK activation and AMPK activating drugs in human studies.

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“…Although AMPK may in some cases promote late-stage tumor growth (Laderoute et al, 2014), multiple lines of evidence suggest AMPK has critical tumor suppressor activities in both humans and experimental models, including mice (Hardie and Alessi, 2013; Shackelford and Shaw, 2009). For example, knockout of AMPKα1 in the mouse accelerates development of c-Myc-driven lymphomas (Faubert et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Degradation of AMPK by a Cancer-Specific Ubiquitin Ligase

Pineda

Ramanathan

Tacer

et al. 2015

Cell

307

333

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SUMMARY AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline, but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.

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5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors

Cited by 61 publications

References 37 publications

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Degradation of AMPK by a Cancer-Specific Ubiquitin Ligase

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