A769662, a novel activator of AMP‐activated protein kinase, inhibits non‐proteolytic components of the 26S proteasome by an AMPK‐independent mechanism

Moreno, Daniel Antunes; Knecht, Erwin; Viollet, Benoı̂t; Sanz, Pascual

doi:10.1016/j.febslet.2008.06.044

Cited by 84 publications

(72 citation statements)

References 23 publications

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“…We also showed that the effect on glucose uptake is likely mediated by the PI3-kinase/Akt/TBC1D1/TBC1D4 signaling pathway. Thus, although we do not know the mechanism by which the PI3-kinase is activated by A-769662, our data suggest that A-769662 has off-target effects as previously shown (34). This should be taken into consideration in future studies involving A-769662.…”

Section: Discussionmentioning

confidence: 63%

“…Previous studies that have used this compound to study the effects on metabolism in cells and phosphorylation of AMPK and ACC in skeletal muscle have used lower (1-300 M) concentrations (9,13,14,34,37,38). However, on the basis of the relatively poor bioavailability of A-769662 in skeletal muscle compared with liver (9), and since our experimental model involved incubated intact skeletal muscles rather than primarily in vitro studies like those previously reported (14, 37), we wanted to create as high a concentration gradient across the sarcolemma as possible.…”

Section: Discussionmentioning

confidence: 99%

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A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

Treebak

Birk

Hansen

et al. 2009

American Journal of Physiology-Cell Physiology

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

Treebak

Birk

Hansen

et al. 2009

American Journal of Physiology-Cell Physiology

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“…6) A latest paper demonstrated that A-769662 was able to inhibit proteasomal function and lead to an arrest of cell cycle progression in an AMPK-independent mannar in mouse embryonic fibroblast (MEF) cells. 20) Therefore, we couldn't rule out the possibility that A-769662 inhibited MCE via inhibition of proteasome activity in 3T3-L1 cells, which needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of A-769662, a Novel Activator of AMP-Activated Protein Kinase, on 3T3-L1 Adipogenesis

Zhou

Wang

Zhu

et al. 2009

Biological & Pharmaceutical Bulletin

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Obesity is a chronic metabolic disorder caused by an imbalance between energy intake and expenditure. It is a major known risk factor for many chronic diseases such as type 2 diabetes, hypertension and atherosclerosis.1) Therefore, it has become a major obstacle of improving human health and life quality. Obesity is characterized by a pathologic growth of adipose tissues, which is intrinsically a consequence of adipocyte hypertrophy and differentiation. 2)Studies on several established immortal preadipocyte cell lines such as 3T3-L1 and 3T3-F442A have greatly facilitated our understanding of adipocyte differentiation, which is a tightly controlled and highly orchestrated event accompanied by expression of multiple transcription factors and adipogenic markers, including the CCAAT/enhancer binding proteins (C/EBPs), the peroxisome proliferator-activated receptors (PPARs), fatty acid synthase (FAS) and the adipocyte-specific fatty acid binding protein (aP2).3,4) Briefly, growth-arrested preadipocytes reenter the cell cycle and undergo one or two rounds of division known as mitotic clonal expansion (MCE), during which an immediate and transient induction of C/EBPb and C/EBPd occurs and is followed by up-regulation of PPARg and C/EBPa, two master transcription factors of adipogenesis. PPARg and C/EBPa further trigger expression of multiple adipogenic genes that synergistically lead to adipocyte phenotype. 4) Tang et al. reported that MCE was a prerequisite for adipogenesis and C/EBPb was required for MCE, 5,6) suggesting the importance of C/EBPb in the initial stage of adipocyte differentiation.AMP-activated protein kinase (AMPK), a serine/threonine kinase consisting of a catalytic subunit a and two regulatory subunits b and g, plays a key role in regulation of fatty acid and glucose homeostasis.7) AMPK activation requires phosphorylation at Thr172 of AMPKa subunit by upstream AMPK kinase. Once activated, AMPK blocks ATP-consuming pathways and stimulates ATP-generating pathways. AMPK acts via phosphorylation of downstream metabolic enzymes and transcription factors.8) Acetyl-CoA carboxylase (ACC), a critical enzyme for lipid biosynthesis, can be phosphorylated and inactivated by AMPK. 9) Inactivation of ACC leads to a decreased production of malonyl CoA, which in turn de-represses carnitine palmitoyl-CoA transferase (CPT1) to increase fatty acid oxidation.10) Previous studies have demonstrated the involvement of AMPK activation in the anti-adipogenic effects of several compounds. 11,12) On the other hand, low-level activation of AMPK is likely to play a role in the development of obesity and diabetes.13) Hence, the function of AMPK activation in adipogenesis needs further investigation.A-769662 is a novel activator of AMPK which activates AMPK directly in vivo and in vitro. 14,15) Previous research demonstrated that A-769662 reduced body weight gain and decreased liver and plasma triglyceride levels via increasing fatty acid oxidation and reducing fatty acid synthesis in vivo.14) However, the effect of A-769662 on ad...

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“…AMPK activators may have other targets than AMPK [43,44]. In this respect, a recent study has demonstrated that AICAR and phenformin cause dephosphorylation of Akt and glycogen synthase kinase-3 (GSK-3) independently of their effects on AMPK activity [45].…”

Section: Page 18 Of 38mentioning

confidence: 99%

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

García-García¹,

Fumarola²,

Navaratnam³

et al. 2010

Biochemical Pharmacology

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMPactivated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP.Here we report that a number of AMPK activators, including the small molecule activator A-769662, markedly sensitize TRAIL-resistant breast cancer cells to TRAIL-induced apoptosis.However, silencing AMPKα1 expression with siRNA or over-expression of DN-AMPKα1 does not inhibit AICAR, glucose deprivation, phenformin or A-769662-induced sensitization to TRAIL. Furthermore, the expression of constitutively active AMPK subunits does not sensitize resistant breast cancer cells to TRAIL-induced apoptosis. The cellular FLICEinhibitory proteins (cFLIP L and cFLIP S ) were significantly down-regulated following exposure to AMPK activators through an AMPK-independent mechanism. Furthermore, in cells over-expressing cFLIP L , sensitization to TRAIL by AMPK activators was markedly reduced. In summary, our results indicate that AMPK activators facilitate the activation by TRAIL of an apoptotic cell death program through a mechanism independent of AMPK and dependent on the down-regulation of cFLIP levels.

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A769662, a novel activator of AMP‐activated protein kinase, inhibits non‐proteolytic components of the 26S proteasome by an AMPK‐independent mechanism

Cited by 84 publications

References 23 publications

A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

Inhibitory Effects of A-769662, a Novel Activator of AMP-Activated Protein Kinase, on 3T3-L1 Adipogenesis

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

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A769662, a novel activator of AMP‐activated protein kinase, inhibits non‐proteolytic components of the 26S proteasome by an AMPK‐independent mechanism

Cited by 84 publications

References 23 publications

A-769662 activates AMPK β1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

A-769662 activates AMPK β1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

Inhibitory Effects of A-769662, a Novel Activator of AMP-Activated Protein Kinase, on 3T3-L1 Adipogenesis

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

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A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle

A-769662 activates AMPK β₁-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle