The Mixed Blessing of AMPK Signaling in Cancer Treatments

2021 ◽  
Author(s):  
Mehrshad Sadria ◽  
Anita Layton ◽  
Deokhwa Seo
Keyword(s):  
Cancer Cells ◽  
Energy Homeostasis ◽  
Signalling Pathways ◽  
Cell Type ◽  
Cancer Treatments ◽  
Ampk Signaling ◽  
Mechanistic Target Of Rapamycin ◽  
Metabolic Signalling ◽  
Mixed Blessing ◽  
Amp Activated Protein Kinase

Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter-intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state. To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with specific focus on AMPK, mTORC, and their modulators. Model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.

scholarly journals AMP-activated protein kinase pathway and bone metabolism

2011 ◽  
Vol 212 (3) ◽  
pp. 277-290 ◽  
Author(s):  
J Jeyabalan ◽  
M Shah ◽  
B Viollet ◽  
C Chenu
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Bone Cells ◽  
Peripheral Tissues ◽  
Ampk Signaling ◽  
Obesity And Diabetes ◽  
Regulate Food Intake ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formationin vitroand the deletion of α or β subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

Lack of AMPKα2 enhances pyruvate dehydrogenase activity during exercise

2007 ◽  
Vol 293 (5) ◽  
pp. E1242-E1249 ◽  
Author(s):  
Ditte K. Klein ◽  
Henriette Pilegaard ◽  
Jonas T. Treebak ◽  
Thomas E. Jensen ◽  
Benoit Viollet ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Energy Homeostasis ◽  
Oxidative Capacity ◽  
Treadmill Running ◽  
Glycolytic Flux ◽  
Ampk Signaling ◽  
Mitochondrial Dna Content ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise

5′-AMP-activated protein kinase (AMPK) was recently suggested to regulate pyruvate dehydrogenase (PDH) activity and thus pyruvate entry into the mitochondrion. We aimed to provide evidence for a direct link between AMPK and PDH in resting and metabolically challenged (exercised) skeletal muscle. Compared with rest, treadmill running increased AMPKα1 activity in α2KO mice (90%, P < 0.01) and increased AMPKα2 activity in wild-type (WT) mice (110%, P < 0.05), leading to increased AMPKα Thr172 (WT: 40%, α2KO: 100%, P < 0.01) and ACCβ Ser227 phosphorylation (WT: 70%, α2KO: 210%, P < 0.01). Compared with rest, exercise significantly induced PDH-E1α site 1 (WT: 20%, α2KO: 62%, P < 0.01) and site 2 (only α2KO: 83%, P < 0.01) dephosphorylation and PDHa [∼200% in both genotypes ( P < 0.01)]. Compared with WT, PDH dephosphorylation and activation was markedly enhanced in the α2KO mice both at rest and during exercise. The increased PDHa activity during exercise was associated with elevated glycolytic flux, and muscles from the α2KO mice displayed marked lactate accumulation and deranged energy homeostasis. Whereas mitochondrial DNA content was normal, the expression of several mitochondrial proteins was significantly decreased in muscle of α2KO mice. In isolated resting EDL muscles, activation of AMPK signaling by AICAR did not change PDH-E1α phosphorylation in either genotype. PDH is activated in mouse skeletal muscle in response to exercise and is independent of AMPKα2 expression. During exercise, α2KO muscles display deranged energy homeostasis despite enhanced glycolytic flux and PDHa activity. This may be linked to decreased mitochondrial oxidative capacity.

scholarly journals EJE PRIZE 2017: Hypothalamic AMPK: a golden target against obesity?

2017 ◽  
Vol 176 (5) ◽  
pp. R235-R246 ◽  
Author(s):  
Miguel López
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Muscle Metabolism ◽  
Hepatic Function ◽  
Energy Balance Equation ◽  
Point Of View ◽  
Current Evidence ◽  
Ampk Signaling ◽  
Brown Adipose ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a cellular gauge that is activated under conditions, such as low energy, increasing energy production and reducing energy waste. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence links hypothalamic AMPK with feeding, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), as well as muscle metabolism, hepatic function and glucose homeostasis. The relevance of these data is interesting from a therapeutic point of view as several agents with potential anti-obesity and/or antidiabetic effects, some currently in clinical use, such as nicotine, metformin and liraglutide are known to act through AMPK, either peripherally or centrally. Furthermore, the orexigenic and weight-gaining effects of the worldwide use of antipsychotic drugs (APDs), such as olanzapine, are also mediated by hypothalamic AMPK. Overall, this evidence makes hypothalamic AMPK signaling an interesting target for the drug development, with its potential for controlling both sides of the energy balance equation, namely feeding and energy expenditure through defined metabolic pathways.

scholarly journals Adenine Inhibits the Growth of Colon Cancer Cells via AMP-Activated Protein Kinase Mediated Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Hsin-Wu Lai ◽  
James Cheng-Chung Wei ◽  
Hung-Chang Hung ◽  
Chun-Che Lin
Keyword(s):  
Colon Cancer ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Ampk Signaling ◽  
Anticancer Effects ◽  
Expression Of Genes ◽  
Amp Activated Protein Kinase

Background. Adenine is involved in a variety of cell biological processes and has been explored for pharmacological uses. Its therapeutic use for managing cancer is of great interest. In the present study, we investigated the anticancer effects of adenine and the underlying mechanism in colon cancer cells. Methods. Cell viability was measured using the MTT assay. Levels of phosphorylation and protein expression were determined using western blotting. qPCR was carried out to determine the changes in mRNA expression of genes of interest. Results. Adenine significantly inhibited the viability of colon cancer cells, HT29 and Caco-2 cells, in a dose-dependent manner. Adenine induced significant apoptosis in HT29 cells, whereas Caco-2 cells exhibited less apoptotic responses. The data showed that adenine activated AMP-activated protein kinase (AMPK) signaling contributing to autophagic cell death through mTOR in both colon cancer cell lines. Conclusions. Our findings suggest that adenine inhibits the growth of colon cancer cells. Anticancer activity of adenine in colon cancer cells is attributable to the activation of apoptotic signaling and in turn the AMPK/mTOR pathway. Adenine represents a natural compound with anticancer potency.

scholarly journals The Mixed Blessing of AMPK Signaling in Cancer Treatments

2021 ◽  
Author(s):  
Mehrshad Sadria ◽  
Deokhwa Seo ◽  
Anita T. Layton
Keyword(s):  
Cancer Treatments ◽  
Ampk Signaling ◽  
Mixed Blessing

scholarly journals AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

2021 ◽  
Vol 9 ◽  
Author(s):  
Dan Yi ◽  
Huan Yu ◽  
Ke Lu ◽  
Changshun Ruan ◽  
Changhai Ding ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Skeletal Development ◽  
Adenosine Monophosphate ◽  
Nuclear Factor Κb ◽  
Energy Control ◽  
Atp Production ◽  
Ampk Signaling ◽  
Energy Sensor ◽  
Cartilage Biology ◽  
Amp Activated Protein Kinase

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) was initially identified as an enzyme acting as an “energy sensor” in maintaining energy homeostasis via serine/threonine phosphorylation when low cellular adenosine triphosphate (ATP) level was sensed. AMPK participates in catabolic and anabolic processes at the molecular and cellular levels and is involved in appetite-regulating circuit in the hypothalamus. AMPK signaling also modulates energy metabolism in organs such as adipose tissue, brain, muscle, and heart, which are highly dependent on energy consumption via adjusting the AMP/ADP:ATP ratio. In clinics, biguanides and thiazolidinediones are prescribed to patients with metabolic disorders through activating AMPK signaling and inhibiting complex I in the mitochondria, leading to a reduction in mitochondrial respiration and elevated ATP production. The role of AMPK in mediating skeletal development and related diseases remains obscure. In this review, in addition to discuss the emerging advances of AMPK studies in energy control, we will also illustrate current discoveries of AMPK in chondrocyte homeostasis, osteoarthritis (OA) development, and the signaling interaction of AMPK with other pathways, such as mTOR (mechanistic target of rapamycin), Wnt, and NF-κB (nuclear factor κB) under OA condition.

scholarly journals Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3263
Author(s):  
Alicia González ◽  
Carolina Alonso-González ◽  
Alicia González-González ◽  
Javier Menéndez-Menéndez ◽  
Samuel Cos ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Protective Effect ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Chemotherapeutic Agents ◽  
Inhibitory Effects ◽  
Anticancer Effect ◽  
Cancer Treatments ◽  
Melatonin Administration ◽  
Effects Of Radiation

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.

scholarly journals Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2956
Author(s):  
Paweł Jóźwiak ◽  
Piotr Ciesielski ◽  
Piotr K. Zakrzewski ◽  
Karolina Kozal ◽  
Joanna Oracz ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Energy Homeostasis ◽  
Glucose Sensor ◽  
Single Gene ◽  
Mitochondrial Proteins ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Inner Mitochondrial Membrane ◽  
Glcnac Transferase ◽  
The Impact

O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT’s role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein partners and O-GlcNAcylated proteins from mitochondria-enriched fraction followed by their analysis by mass spectrometry. Moreover, we analyzed the impact of mOGT dysregulation on mitochondrial activity and cellular metabolism using a variety of biochemical assays. We found that mitochondrial OGT expression is glucose-dependent. Elevated mOGT expression affected the mitochondrial transmembrane potential and increased intramitochondrial ROS generation. Moreover, mOGT up-regulation caused a decrease in cellular ATP level. We identified many mitochondrial proteins as mOGT substrates. Most of these proteins are localized in the mitochondrial matrix and the inner mitochondrial membrane and participate in mitochondrial respiration, fatty acid metabolism, transport, translation, apoptosis, and mtDNA processes. Our findings suggest that mOGT interacts with and modifies many mitochondrial proteins, and its dysregulation affects cellular bioenergetics and mitochondria function.

scholarly journals Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

2021 ◽  
Vol 7 (6) ◽  
pp. eabd3311
Author(s):  
Gerda Kildisiute ◽  
Waleed M. Kholosy ◽  
Matthew D. Young ◽  
Kenny Roberts ◽  
Rasa Elmentaite ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Developmental Stages ◽  
Neuroblastoma Cells ◽  
Cell Type ◽  
Adrenal Cell ◽  
Universal Feature ◽  
Principal Finding

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

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