Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Dengler, Franziska

doi:10.3390/ijms21072428

Cited by 88 publications

(68 citation statements)

References 122 publications

(189 reference statements)

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“…Several HIF-independent metabolic regulatory mechanisms may be considered. Hypoxia-mediated activation of AMP-activated protein kinase (AMPK) reduces ATP demand in cells and contributes to cell survival in hypoxia (Dengler, 2020;Wheaton and Chandel, 2011). While the effects of hypoxic AMPK activation on decreasing protein synthesis are well established, direct measurements of the effects of AMPK on metabolic flux in hypoxia are sparse.…”

Section: Discussionmentioning

confidence: 99%

MYC overrides HIF to regulate proliferating primary cell metabolism in hypoxia

Copeland

Olenchock

Young

et al. 2020

Preprint

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Hypoxia is an important environmental stimulus that causes transcriptional and metabolic reprogramming in cells to facilitate their survival. Here, we performed stable isotope tracing and metabolic flux analyses of proliferating primary cells in hypoxia. Despite activation of the hypoxia-inducible factor (HIF) transcriptional program and up-regulation of glycolytic genes, glycolytic flux was decreased in hypoxic cells in our models. No evidence for increased glutaminolysis or reductive carboxylation was observed. While pharmacologic stabilization of HIF in normoxia with the prolyl hydroxylase inhibitor molidustat did increase glycolytic flux as expected, hypoxia abrogated this effect. Together, these data suggest that primary cell bioenergetic metabolism is closely coupled to cell proliferation rate and that other regulatory factors override the effects of HIF-dependent up-regulation of glycolytic gene expression on glycolytic flux.

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Section: Discussionmentioning

confidence: 99%

MYC overrides HIF to regulate proliferating primary cell metabolism in hypoxia

Copeland

Olenchock

Young

et al. 2020

Preprint

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“…To withstand the hypoxic conditions, complex gene regulation is involved in endometriosis development [41]. Hypoxia is the main stimulus that activates AMPK [42,43]. AMPK stimulates signaling essential for survival when cells are exposed to a variety of stressful environments, including hypoxia [44,45].…”

Section: Accepted Articlementioning

confidence: 99%

Tetraspanin 1 promotes endometriosis leading to ovarian clear cell carcinoma

et al. 2021

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Ovarian clear cell carcinoma (OCCC) reportedly develops from endometriosis. However, the molecular mechanism underlying its malignant progression to OCCC remains elusive. This study aimed to identify an essential gene in the malignant transformation of endometriosis to OCCC. We performed RNA sequencing in formalin‐fixed, paraffin‐embedded (FFPE) tissues of endometriosis (n = 9), atypical endometriosis (AtyEm) (n = 18), adjacent endometriosis to OCCC (AdjEm) (n = 7), and OCCC (n = 17). We found that tetraspanin 1 (TSPAN1) mRNA level was significantly increased by 2.4‐ (DESeq2) and 3.4‐fold (edgeR) in AtyEm and by 80.7‐ (DESeq2) and 101‐fold (edgeR) in OCCC relative to endometriosis. We confirmed that TSPAN1 protein level was similarly overexpressed in OCCC tissues and cell lines. In immortalized endometriosis cell lines, TSPAN1 overexpression enhanced cell growth and invasion. Mechanistically, TSPAN1 triggered AMP‐activated protein kinase (AMPK) activity, promoting endometriosis and cell growth. Upregulated levels of TSPAN1 are considered an early event in the development of high‐risk endometriosis that could progress to ovarian cancer. Our study suggests the potential of TSPAN1 as a screening candidate for high‐risk endometriosis.

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“…One important signaling pathway that negatively regulates mTORC1 activity is the liver kinase B1 (LKB1)/ AMP-activated protein kinase (AMPK) pathway [67]. AMPK is a cellular energy sensor activated in various conditions that deplete cellular energy, such as nutrient deprivation or hypoxia [68,69]. Phosphorylation of AMPK at T172 in the activation loop is required for its kinase activity and is mediated by LKB1, the upstream serine/threonine kinase of AMPK [70].…”

Section: Regulation Of the Pi3k/akt/mtor Pathway In Normal Hematopoiesismentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Cited by 88 publications

References 122 publications

MYC overrides HIF to regulate proliferating primary cell metabolism in hypoxia

MYC overrides HIF to regulate proliferating primary cell metabolism in hypoxia

Tetraspanin 1 promotes endometriosis leading to ovarian clear cell carcinoma

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

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