AMPK activation protects against prostate cancer by inducing a catabolic cellular state

Penfold, Lucy; Woods, Angela; Pollard, Alice; Arizanova, Julia; Pascual-Navarro, Eneko; Muckett, Phillip; Dore, Marian; Montoya, Alex; Whilding, Chad; Fets, Louise; Mokochinski, João Benhur; Constantin, Theodora A.; Varela-Carver, Anabel; Leach, Damien A.; Bevan, Charlotte L.; Nikitin, Alexander Yu.; Hall, Zoe; Carling, David

doi:10.1016/j.celrep.2023.112396

Cited by 12 publications

(11 citation statements)

References 60 publications

(95 reference statements)

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“…Adipogenesis requires convergence of many signalling pathways, all resulting in the initiation of transcription factor binding, followed by chromatin remodelling and, ultimately, adipogenic gene expression [ 8 , 24 ]. AMPK is known to interact with and/or modulate the expression of many of these factors, including ChrEBP, SREBP1-c/2, PPARγ and PGC1α, with documented AMPK-dependent repression of translocation, binding and/or expression in each case [ 42 , 48–54 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this study we employ the direct AMPK activator BI-9774 [ 42 ] in a concentration-dependent manner, both throughout differentiation and via a ‘pulse’ treatment during adipogenic initiation. In parallel, we examine the effect of pharmacological inhibition of ACC to determine which, if any, of the effects of AMPK activation on adipogenesis are mediated through ACC inhibition.…”

Section: Introductionmentioning

confidence: 99%

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AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes

Bustraan,

Bennett,

Whilding

et al. 2024

Biochemical Journal

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Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells (mADSCs) were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. In order to determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes

Bustraan,

Bennett,

Whilding

et al. 2024

Biochemical Journal

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“…Knockout of ERRα prevents PGC1α from inhibiting invasion, suggesting that the PGC1α/ERRα axis acts as an antagonist to the progression of PC metastasis ( 146 , 152 ). Furthermore, AMPK, a metabolic regulator in PC, safeguards against cancer progression in mice models ( 154 – 156 ). Activation of AMPK leads to increased expression of PGC1α and its downstream targets, promoting a switch to a more oxidative and catabolic metabolism and opposing the pro-tumorigenic program of increased lipogenesis ( 154 ).…”

Section: Roles Of Pgc1α In Cancer Cellsmentioning

confidence: 99%

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

Wang,

Peng,

Yang

et al. 2024

Front. Oncol.

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PGC1α, a central player in mitochondrial biology, holds a complex role in the metabolic shifts seen in cancer cells. While its dysregulation is common across major cancers, its impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas in others, overexpression escalates respiration and aggression. PGC1α’s interactions with distinct signaling pathways and transcription factors further diversify its roles, often in a tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1α-targeted approaches. This review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1α in diverse cancers. We examined PGC1α’s tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator. In cancers where PGC1α is tumor-suppressive, reinstating its levels could halt cell proliferation and invasion, and make the cells more receptive to chemotherapy. In cancers where the opposite is true, halting PGC1α’s upregulation can be beneficial as it promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype. Thus, to target PGC1α effectively, understanding its nuanced role in each cancer subtype is indispensable. This can pave the way for significant strides in the field of oncology.

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“…In vivo AMPK activation inhibits prostate cancer development by suppressing de novo lipogenesis ( Zadra et al ., 2014 ). Additionally, AMPK activation suppresses prostate cancer progression and metastasis by decreasing lipogenesis via PGC1α activation ( Penfold et al ., 2023 ).…”

Section: Ampk and Tumor Cellsmentioning

confidence: 99%

AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer

Pokhrel,

Acharya,

Mishra

et al. 2024

Biomol Ther (Seoul)

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All cells are equipped with intricate signaling networks to meet the energy demands and respond to the nutrient availability in the body. AMP-activated protein kinase (AMPK) is among the most potent regulators of cellular energy balance. Under ATP -deprived conditions, AMPK phosphorylates substrates and affects various biological processes, such as lipid/glucose metabolism and protein synthesis. These actions further affect the cell growth, death, and functions, altering the cellular outcomes in energy-restricted environments. AMPK plays vital roles in maintaining good health. AMPK dysfunction is observed in various chronic diseases, making it a promising target for preventing and alleviating such diseases. Herein, we highlight the different AMPK functions, especially in allergy, aging, and cancer, to facilitate the development of new therapeutic approaches in the future.

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AMPK activation protects against prostate cancer by inducing a catabolic cellular state

Cited by 12 publications

References 60 publications

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

AMPK Alchemy: Therapeutic Potentials in Allergy, Aging, and Cancer

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