AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965

Dite, Toby A.; Langendorf, Christopher G.; Hoque, Ashfaqul; Galić, Sandra; Rebello, Richard J.; Ovens, Ashley J.; Lindqvist, Lisa; Ngoei, Kevin R.W.; Ling, Naomi X.Y.; Furic, Luc; Kemp, Bruce E.; Scott, John W.; Oakhill, Jonathan S.

doi:10.1074/jbc.ra118.003547

Cited by 104 publications

(121 citation statements)

References 63 publications

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“…It is important to note here that the inhibitor affects downstream effector, but not AMPK phosphorylation per se. 29 Collectively, our data suggest that Nischarin disruption promotes breast tumor development and AMPK signaling is important for Nischarin-mediated suppression of breast tumor.…”

Section: Samples Gave Two Bands; One Represents 250 Kda Full-lengthmentioning

confidence: 70%

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Dong

Ruiz-Calderon

Rathinam

et al. 2019

Intl Journal of Cancer

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Previously, our lab discovered the protein Nischarin and uncovered its role in regulating cell migration and invasion via its interactions with several proteins. We subsequently described a role for Nischarin in breast cancer, in which it is frequently underexpressed. To characterize Nischarin's role in breast tumorigenesis and mammary gland development more completely, we deleted a critical region of the Nisch gene (exons 7–10) from the mouse genome and observed the effects. Mammary glands in mutant animals showed delayed terminal end bud formation but did not develop breast tumors spontaneously. Therefore, we interbred the animals with transgenic mice expressing the mouse mammary tumor virus‐polyoma middle T‐antigen (MMTV‐PyMT) oncogene. The MMTV‐PyMT mammary glands lacking Nischarin showed increased hyperplasia compared to wild‐type animal tissues. Furthermore, we observed significantly increased tumor growth and metastasis in Nischarin mutant animals. Surprisingly, Nischarin deletion decreased activity of AMPK and subsequently its downstream effectors. Given this finding, we treated these animals with metformin, which enhances AMPK activity. Here, we show for the first time, metformin activates AMPK signaling and inhibits tumor growth of Nischarin lacking PyMT tumors suggesting a potential use for metformin as a cancer therapeutic, particularly in the case of Nischarin‐deficient breast cancers.

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Section: Samples Gave Two Bands; One Represents 250 Kda Full-lengthmentioning

confidence: 70%

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Dong

Ruiz-Calderon

Rathinam

et al. 2019

Intl Journal of Cancer

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“…With the recent identification of more specific AMPK inhibitors, such as SBI-0206965 (REF. 199 ), it will be interesting to examine whether delivery of AMPK inhibitors into the central nervous system might suppress appetite and promote weight loss.…”

Section: ) (Table 1)mentioning

confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

464

405

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Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elucidate the role of AMPK in these beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Commented [WS2]: Au: "The optimal consensus motif of AMPK substrates has been established (BOX 3)" OK?

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“…This transient increase in peak glucose levels was attenuated by pre-treatment with AMPK/Uncoordinated (Unc)-51-like kinase (ULK-1) inhibitor SBI-0206965 (3 mg kg -1 ; Fig. 2A), which inhibits AMPK in vitro at nanomolar concentrations (18). Previous studies have shown that suppression or activation of hypothalamic AMPK activity can attenuate or stimulate hepatic glucose production, respectively (19-21), indicating that hypothalamic AMPK activity regulates hepatic glucose production (HGP).…”

Section: Resultsmentioning

confidence: 99%

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

Am¹,

Malekizadeh²,

Walker³

et al. 2019

Preprint

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AMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production.Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps.Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemichypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

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AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965

Cited by 104 publications

References 63 publications

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

AMP-activated protein kinase: the current landscape for drug development

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

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