AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK ...targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK and, importantly, also into the sites bound by small molecule activators, thus providing a path for improved drugs.
AMPK is a highly conserved central regulator of cellular and organismal metabolism, which restores energy balance during low-energy conditions such as following starvation or mitochondria stress. Garcia and Shaw review recent advances in AMPK regulation and function, including identification of downstream effectors through which AMPK mechanistically restores metabolic homeostasis.
The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK ...activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.
Trefts and Shaw review the latest advances in studies of the AMPK signaling pathway, a central energy-sensing kinase that promotes catabolism and inhibits anabolism to limit cell growth and promote cell survival under conditions of low nutrients and low cellular energy. Highlights include new intersections with mTOR, lysosomes, and mitochondria.
Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core ...autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.
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•ULK1 phosphorylates multiple autophagy components, including VPS34 on Ser249•SBI-0206965 is a highly selective ULK1 kinase inhibitor that blocks autophagy•SBI-0206965 combined with starvation or mTOR inhibition leads to ULK1 degradation•SBI-0206965 synergizes with mTOR inhibition to induce cell death
ULK1 is a serine/threonine kinase that initiates autophagy in response to nutrient deprivation. Egan et al. define ULK1’s consensus phosphorylation motif, demonstrate that ULK1 phosphorylates several autophagy components, and develop a ULK1 small molecule inhibitor (SBI-0206965). SBI-0206965 synergizes with mTOR inhibition to enhance apoptosis in tumor cells, suggesting therapeutic opportunities.
AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. Here we demonstrate that AMPK interacts with and directly ...phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2). Ser372 phosphorylation of SREBP-1c by AMPK is necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin-resistant LDL receptor-deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c- and -2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.
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▴ AMPKα subunit interacts with and directly phosphorylates SREBP-1c and SREBP-2 ▴ Phosphorylation of SREBP-1c by AMPK represses de novo lipogenesis in hepatocytes ▴ AMPK inhibits SREBP cleavage and gene transcription in insulin-resistant mice ▴ SREBP suppression by polyphenols attenuates hepatic steatosis and atherosclerosis
One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has ...critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. Here we review a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of newly identified downstream effectors of AMPK.
Glucose metabolism and cancer Shaw, Reuben J
Current opinion in cell biology,
12/2006, Letnik:
18, Številka:
6
Journal Article
Recenzirano
The first identified biochemical hallmark of tumor cells was a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis. We now know that much of this metabolic conversion is ...controlled by specific transcriptional programs. Recent studies suggest that activation of the hypoxia-inducible factor (HIF) is a common consequence of a wide variety of mutations underlying human cancer. HIF stimulates expression of glycolytic enzymes and decreases reliance on mitochondrial oxidative phosphorylation in tumor cells, which occurs even under aerobic conditions. In addition, recent efforts have also connected the master metabolic regulator AMP-activated protein kinase (AMPK) to several human tumor suppressors. Several promising therapeutic strategies based on modulation of AMPK, HIF and other metabolic targets have been proposed to exploit the addiction of tumor cells to increased glucose uptake and glycolysis.
Metabolic homeostasis requires that cellular energy levels are adapted to environmental cues. This adaptation is largely regulated at the transcriptional level, through the interaction between ...transcription factors, coregulators, and the basal transcriptional machinery. Coregulators, which function as both metabolic sensors and transcriptional effectors, are ideally positioned to synchronize metabolic pathways to environmental stimuli. The balance between inhibitory actions of corepressors and stimulatory effects of coactivators enables the fine-tuning of metabolic processes. This tight regulation opens therapeutic opportunities to manage metabolic dysfunction by directing the activity of cofactors toward specific transcription factors, pathways, or cells/tissues, thereby restoring whole-body metabolic homeostasis.
The review by Mouchiroud et al. discusses transcriptional coregulators. Acting as both metabolic sensors and transcriptional effectors, they are ideally positioned to fine-tune metabolic processes in response to environmental stimuli.
Replicative crisis is a senescence-independent process that acts as a final barrier against oncogenic transformation by eliminating pre-cancerous cells with disrupted cell cycle checkpoints
. It ...functions as a potent tumour suppressor and culminates in extensive cell death. Cells rarely evade elimination and evolve towards malignancy, but the mechanisms that underlie cell death in crisis are not well understood. Here we show that macroautophagy has a dominant role in the death of fibroblasts and epithelial cells during crisis. Activation of autophagy is critical for cell death, as its suppression promoted bypass of crisis, continued proliferation and accumulation of genome instability. Telomere dysfunction specifically triggers autophagy, implicating a telomere-driven autophagy pathway that is not induced by intrachromosomal breaks. Telomeric DNA damage generates cytosolic DNA species with fragile nuclear envelopes that undergo spontaneous disruption. The cytosolic chromatin fragments activate the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway and engage the autophagy machinery. Our data suggest that autophagy is an integral component of the tumour suppressive crisis mechanism and that loss of autophagy function is required for the initiation of cancer.
The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, ...making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
► Phenformin is a mitochondrial inhibitor that selectively kills LKB1−/− NSCLC cells ► LKB1−/− NSCLC cells exhibit defective mitochondria and ROS following phenformin ► Phenformin improves tumors and survival in KrasG12DLkb1−/−, not KrasG12Dp53−/− mice ► eIF2α signaling markers are AMPK-independent biomarkers of biguanide treatment
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