Targeting LKB1 in cancer – exposing and exploiting vulnerabilities

Momcilovic, Milica; Shackelford, David B.

doi:10.1038/bjc.2015.261

Cited by 85 publications

(87 citation statements)

References 136 publications

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“…Meanwhile, LKB1 is capable of triggering transcriptional reprogramming via phosphorylation on remaining AMPK related substrates, in order to regulate cell adhesion, longevity and expansion [40]. On the other hand, the molecular basis that leads to LKB1 enzymatic activation remains to be rarely discussed.…”

Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning

confidence: 99%

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Cheng

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.

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Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning

confidence: 99%

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Cheng

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…LKB1 can phosphorylate downstream AMPK at threonine 172 to activate AMPK. LKB1 is discovered to be the key upstream activator of the AMPK 25 . AMPK is a serine/threonine protein kinase, which is widely existed in eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

Odanacatib Inhibits Resistin-induced Hypertrophic H9c2 Cardiomyoblast Cells Through LKB1/AMPK Pathway

Zheng

Liu

Cheng

et al. 2017

Braz. arch. biol. technol.

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“…However, the increased metabolic activity stimulated by transformation imposes additional stresses on tumor cells such as nutrient depletion and redox imbalance, which must be countered in order for tumors to survive and grow. The Liver Kinase B1 (LKB1)/AMPactivated protein kinase (AMPK) pathway contributes to tumor cell survival by promoting cellular sensing of and adaptation to such bioenergetic stress (3). Inactivation of LKB1 in cancer, conversely, promotes anabolic metabolic reprogramming at the expense of metabolic flexibility (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Repression of LKB1 bymiR-17∼92sensitizesMYC-dependent lymphoma to biguanide treatment

Izreig

Gariepy

Donayo

et al. 2019

Preprint

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One Sentence Summary: miR-17~92 expression in Myc + tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.Abstract: Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA cluster miR-17~92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides.Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate that Myc + lymphoma cells with elevated miR-17~92 expression display increased sensitivity to biguanide treatment both in cell viability assays in vitro and tumor growth assays in vivo. This increased biguanide sensitivity is driven by miR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration in miR-17~92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17~92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17~92 expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors.

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Targeting LKB1 in cancer – exposing and exploiting vulnerabilities

Cited by 85 publications

References 136 publications

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Odanacatib Inhibits Resistin-induced Hypertrophic H9c2 Cardiomyoblast Cells Through LKB1/AMPK Pathway

Repression of LKB1 bymiR-17∼92sensitizesMYC-dependent lymphoma to biguanide treatment

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