AMP-Activated Protein Kinase: Friend or Foe in Cancer?

Vara-Ciruelos, Diana; Dandapani, Madhumita; Hardie, D. Grahame

doi:10.1146/annurev-cancerbio-030419-033619

Cited by 24 publications

(29 citation statements)

References 85 publications

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“…Overall, although AMPK was initially suggested as a tumor suppressor, there is ample evidence that this enzyme could be, instead, a tumor promoter [ 83 , 84 ]. This notion is based on its ability to control the metabolic reprogramming of cancer cells under stress circumstances as those occurring in the tumor microenvironment.…”

Section: Metabolic Changes In Cancer Developmentmentioning

confidence: 99%

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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Uncontrolled proliferation is a feature defining cancer and it is linked to the ability of cancer cells to effectively adapt their metabolic needs in response to a harsh tumor environment. Metabolic reprogramming is considered a hallmark of cancer and includes increased glucose uptake and processing, and increased glutamine utilization, but also the deregulation of lipid and cholesterol-associated signal transduction, as highlighted in recent years. In the first part of the review, we will (i) provide an overview of the major types of lipids found in eukaryotic cells and their importance as mediators of intracellular signaling pathways (ii) analyze the main metabolic changes occurring in cancer development and the role of oncogenic signaling in supporting aberrant lipid metabolism and (iii) discuss combination strategies as powerful new approaches to cancer treatment. The second part of the review will address the emerging role of CK2, a conserved serine/threonine protein kinase, in lipid homeostasis with an emphasis regarding its function in lipogenesis and adipogenesis. Evidence will be provided that CK2 regulates these processes at multiple levels. This suggests that its pharmacological inhibition combined with dietary restrictions and/or inhibitors of metabolic targets could represent an effective way to undermine the dependency of cancer cells on lipids to interfere with tumor progression.

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Section: Metabolic Changes In Cancer Developmentmentioning

confidence: 99%

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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“…In addition, somatic mutations in STK11 are now known to occur quite frequently in non-inherited cancers. For example, the gene is mutated in 10–20% of all cases of human lung cancer [ 1 , 140 , 141 , 142 ].…”

Section: Is Ampk a Tumour Suppressor Or A Tumour Promoter?mentioning

confidence: 99%

“…The cBioPortal database [ 159 , 160 ] provides a user-friendly platform to interrogate genetic changes occurring in human cancers for any particular gene, based on the numerous genomic studies of different cancer types that have been performed. Recent analyses of this database [ 1 , 140 , 161 ] revealed that, while the PRKAA2 gene encoding AMPK-α2 is often mutated in human cancers, the PRKAA1 gene encoding AMPK-α1 (also, interestingly, the PRKAB2 gene encoding AMPK-β2) is often amplified instead. While not providing conclusive proof, these results suggest that, if anything, AMPK-α2 may act as a tumour suppressor in human cancers, while AMPK-α1 (and -β2) are more likely to represent tumour-promoting genes.…”

Section: Is Ampk a Tumour Suppressor Or A Tumour Promoter?mentioning

confidence: 99%

“…For reasons that remain unclear, mutations in the PRKAA2 gene are particularly frequent in human skin cancer and melanoma, where, in several different studies, they occurred in 10–23% of cases, while amplification of PRKAA1 is common in adenocarcinoma and squamous cell carcinoma of the lung, where it has been found to occur in 8–11% of cases [ 140 ]. Although the proportion of the cancer mutations in PRKAA2 that cause loss-of-function is not yet clear, the occurrence of frequent mutations suggests that, if anything, AMPK-α2 is acting as a tumour suppressor.…”

Section: Is Ampk a Tumour Suppressor Or A Tumour Promoter?mentioning

confidence: 99%

“…Interestingly, in the TCGA study [ 163 ] there was a significant mutual exclusion between amplification of PRKAA1 and mutations in KRAS ( p < 0.005), but a significant co-occurrence with mutations in TP53 ( p < 0.001) [ 1 ]. In the 22 cases of lung adenocarcinoma with amplification of PRKAA1 , only 3 were not also associated with loss-of-function mutations in TP53 [ 140 ]. Thus, amplification of AMPK-α1 (and normal function of LKB1) seems to be selected for in tumours driven by the loss of p53 function—why should this be?…”

Section: Is Ampk a Tumour Suppressor Or A Tumour Promoter?mentioning

confidence: 99%

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AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

Russell

Hardie

2020

IJMS

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AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers.

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Lysosomes: multifunctional compartments ruled by a complex regulatory network

2022

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More than 50 years have passed since Nobel laureate Cristian de Duve described for the first time the presence of tiny subcellular compartments filled with hydrolytic enzymes: the lysosome. For a long time, lysosomes were deemed simple waste bags exerting a plethora of hydrolytic activities involved in the recycling of biopolymers, and lysosomal genes were considered to just be simple housekeeping genes, transcribed in a constitutive fashion. However, lysosomes are emerging as multifunctional signalling hubs involved in multiple aspects of cell biology, both under homeostatic and pathological conditions. Lysosomes are involved in the regulation of cell metabolism through the mTOR/TFEB axis. They are also key players in the regulation and onset of the immune response. Furthermore, it is becoming clear that lysosomal hydrolases can regulate several biological processes outside of the lysosome. They are also implicated in a complex communication network among subcellular compartments that involves intimate organelle‐to‐organelle contacts. Furthermore, lysosomal dysfunction is nowadays accepted as the causative event behind several human pathologies: low frequency inherited diseases, cancer, or neurodegenerative, metabolic, inflammatory, and autoimmune diseases. Recent advances in our knowledge of the complex biology of lysosomes have established them as promising therapeutic targets for the treatment of different pathologies. Although recent discoveries have started to highlight that lysosomes are controlled by a complex web of regulatory networks, which in some cases seem to be cell‐ and stimuli‐dependent, to harness the full potential of lysosomes as therapeutic targets, we need a deeper understanding of the little‐known signalling pathways regulating this subcellular compartment and its functions.

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AMP-Activated Protein Kinase: Friend or Foe in Cancer?

Cited by 24 publications

References 85 publications

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

Lysosomes: multifunctional compartments ruled by a complex regulatory network

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