Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab

Zulato, Elisabetta; Bergamo, Francesca; Paoli, Angela De; Griguolo, Gaia; Esposito, Giovanni; Salvo, Gian Luca De; Mescoli, Claudia; Rugge, Massimo; Nardin, Margherita; Grazia, L; Lonardi, Sara; Indraccolo, Stefano; Zagonel, Vittorina

doi:10.1038/bjc.2014.274

Cited by 42 publications

(36 citation statements)

References 33 publications

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“…AMPK activation has been investigated in fresh frozen and archival tumor tissue from numerous cancer sites, including prostate (63, 71, 72), breast (73, 74), head and neck (75), colorectal (76, 77), gastric (78, 79), liver (80), lung (81–83), ovary (84), and kidney (85, 86). Table 1 summarizes the population-based studies of AMPK activation, measured by protein expression of phosphorylated AMPKα1 (p-AMPKα1, n=16 studies) or its phosphorylated substrate ACC (p-ACC, n=6 studies), with cancer prognosis and clinicopathologic features.…”

Section: Ampk Role In Cancer: Human Studiesmentioning

confidence: 99%

“…Table 1 summarizes the population-based studies of AMPK activation, measured by protein expression of phosphorylated AMPKα1 (p-AMPKα1, n=16 studies) or its phosphorylated substrate ACC (p-ACC, n=6 studies), with cancer prognosis and clinicopathologic features. Of the 13 studies reporting on p-AMPKα1 at Thr172 and overall, cancer-specific, or progression-free survival, 8 studies found that AMPK activation was associated with improved prognosis among head and neck (75), colorectal (76, 77), gastric (79), liver (80), lung (81), and kidney (85, 86) cancer patients either within the entire study population or within subgroups. Consistent with the findings for p-AMPKα1 at Thr172, one additional study of lung cancer found that higher expression of p-AMPKα1 at Ser485, which inhibits AMPK signaling (14), was associated with shorter survival (82).…”

Section: Ampk Role In Cancer: Human Studiesmentioning

confidence: 99%

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

Zadra

Batista

Loda

2015

Molecular Cancer Research

173

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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Section: Ampk Role In Cancer: Human Studiesmentioning

confidence: 99%

Section: Ampk Role In Cancer: Human Studiesmentioning

confidence: 99%

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

Zadra

Batista

Loda

2015

Molecular Cancer Research

173

162

View full text Add to dashboard Cite

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“…ies, and a number of known chemotherapeutic drugs are associated with the activation of AMPK (39,40).…”

Section: Slc13a5 Suppression Inhibits Hepatoma Cell Proliferationmentioning

confidence: 99%

Silencing of solute carrier family 13 member 5 disrupts energy homeostasis and inhibits proliferation of human hepatocarcinoma cells

Choi

et al. 2017

Journal of Biological Chemistry

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The solute carrier family 13 member 5 (SLC13A5), a sodiumcoupled citrate transporter, plays a key role in importing citrate from the circulation into liver cells. Recent evidence has revealed that SLC13A5 deletion protects mice from high-fat diet-induced hepatic steatosis and that mutation of the SLC13A5 orthologues in Drosophila melanogaster and Caenorhabditis elegans promotes longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, whether perturbation of SLC13A5 affects the metabolism and malignancy of hepatocellular carcinoma is unknown. Here, we sought to determine whether SLC13A5 regulates hepatic energy homeostasis and proliferation of hepatoma cells. RNAi-mediated silencing of SLC13A5 expression in two human hepatoma cell lines, HepG2 and Huh7, profoundly suppressed cell proliferation and colony formation, and induced cell cycle arrest accompanied by increased expression of cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin B1. Furthermore, such suppressive effects were also observed on the growth of HepG2 cell-derived xenografts expressing SLC13A5-shRNA in nude mice. Metabolically, knockdown of SLC13A5 in HepG2 and Huh7 cells was associated with a decrease in intracellular levels of citrate, the ratio of ATP/ADP, phospholipid content, and ATP citrate lyase expression. Moreover, both in vitro and in vivo assays demonstrated that SLC13A5 depletion promotes activation of the AMP-activated protein kinase, which was accompanied by deactivation of oncogenic mechanistic target of rapamycin signaling. Together, our findings expand the role of SLC13A5 from facilitating hepatic energy homeostasis to influencing hepatoma cell proliferation and suggest a potential role of SLC13A5 in the progression of human hepatocellular carcinoma.Metabolic reprogramming has long been regarded as a hallmark of cancer, through which cancer cells switch from oxidative phosphorylation to glycolysis for ATP production even in microenvironments with sufficient oxygen (1, 2). To accommodate the challenge of rapid proliferation, cancer cell metabolism is remodeled to increase the biosynthesis of macromolecules including nucleotides, proteins, and lipids as building blocks of new cells (3,4). Although the precise mechanisms underlying this metabolic reprogramming remain elusive, malignant cells often have perturbed metabolism that allows for the accumulation of many metabolic intermediates facilitating the production of cellular building materials (4,5). Numerous studies have demonstrated that the use of glycolysis and the tricarboxylic acid (TCA) 2 cycle intermediates for biosynthesis is a key feature of altered metabolism in cancer cells (6, 7). Among others, citrate, an intermediate metabolite located at the crossroads of glucose metabolism and energy production, is an important sensor of energy homeostasis (8).Accumulating evidence suggests that citrate is involved in both physiological and pathophysiological processes including histone acetylation, insulin secretion, inflammation, ca...

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“…Interestingly, AMPK activators retarded growth of colorectal cancer (CRC) cell lines and prevented colitis-associated carcinogenesis in mice by inducing caspase-3 cleavage-mediated apoptosis of cancer cells [10][11][12]. Of particular interest, AMPK activation in human intestinal tissues is associated with superior prognosis in CRC patients [13]. Therefore, AMPK has been proposed as a drug target for CRC chemoprevention [14].…”

mentioning

confidence: 99%