Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Ma, Teng; Tian, Xiao; Zhang, Baoding; Li, Mengqi; Wang, Yu; Yang, Chunyan; Wu, Jianfeng; Wei, Xiaoyan; Qu, Qi; Yu, Yaxin; Long, Shating; Feng, Jin-Wei; Li, Chun; Zhang, Cixiong; Xie, Changchuan; Wu, Yaying; Xu, Zheni; Chen, Junjie; Yu, Yongsheng; Huang, Xi; He, Ying; Yao, Luming; Zhang, Lei; Zhu, Maoshu; Wang, Wen; Wang, Zhichao; Zhang, Mingliang; Bao, Yuqian; Jia, Weiping; Lin, Shu-Yong; Ye, Zhiyun; Piao, Hulin; Deng, Xianming; Zhang, Chen-Song

doi:10.1038/s41586-022-04431-8

Cited by 225 publications

(174 citation statements)

References 69 publications

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“…6M ). Researchers have found that MET activates AMPK through PEN2/ATP6AP1/v-ATPase/Ragularor/AXIN/LKB1 pathway [ 41 ], and AMP drives AXIN to directly tether LKB1 to phosphorylate AMPK [ 34 ]. According to these factors, the scientific questions involved need further exploration including the identification of the molecule that relieves the direct binding and inhibition of AMPK by NFE2L1 during AMPK activation, whether NFE2L1 is degraded by the lysosomal pathway, and whether the oxidative stress regulates energy metabolism through the NFE2L1-AMPK axis.…”

Section: Discussionmentioning

confidence: 99%

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

et al. 2022

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The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.

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Section: Discussionmentioning

confidence: 99%

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

et al. 2022

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“…underline an alternative mechanism of action played by metformin in an AMP-independent manner. In fact, they underline the ability of metformin to target PEN2, which in turn induces the activation of lysosomal AMPK ( 62 ). In view of these observations and given the key role of LKB1 in controlling metabolism homeostasis, different studies have indicated the possibility of using the biguanide metformin (and the related drug phenformin) in combination with first-line drugs, to induce metabolic stress in vitro and in vivo in cells lacking LKB1.…”

Section: Targeting Lkb1 In Metabolismmentioning

confidence: 99%

LKB1: Can We Target an Hidden Target? Focus on NSCLC

et al. 2022

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LKB1 (liver kinase B1) is a master regulator of several processes such as metabolism, proliferation, cell polarity and immunity. About one third of non-small cell lung cancers (NSCLCs) present LKB1 alterations, which almost invariably lead to protein loss, resulting in the absence of a potential druggable target. In addition, LKB1-null tumors are very aggressive and resistant to chemotherapy, targeted therapies and immune checkpoint inhibitors (ICIs). In this review, we report and comment strategies that exploit peculiar co-vulnerabilities to effectively treat this subgroup of NSCLCs. LKB1 loss leads to an enhanced metabolic avidity, and treatments inducing metabolic stress were successful in inhibiting tumor growth in several preclinical models. Biguanides, by compromising mitochondria and reducing systemic glucose availability, and the glutaminase inhibitor telaglenastat (CB-839), inhibiting glutamate production and reducing carbon intermediates essential for TCA cycle progression, have provided the most interesting results and entered different clinical trials enrolling also LKB1-null NSCLC patients. Nutrient deprivation has been investigated as an alternative therapeutic intervention, giving rise to interesting results exploitable to design specific dietetic regimens able to counteract cancer progression. Other strategies aimed at targeting LKB1-null NSCLCs exploit its pivotal role in modulating cell proliferation and cell invasion. Several inhibitors of LKB1 downstream proteins, such as mTOR, MEK, ERK and SRK/FAK, resulted specifically active on LKB1-mutated preclinical models and, being molecules already in clinical experimentation, could be soon proposed as a specific therapy for these patients. In particular, the rational use in combination of these inhibitors represents a very promising strategy to prevent the activation of collateral pathways and possibly avoid the potential emergence of resistance to these drugs. LKB1-null phenotype has been correlated to ICIs resistance but several studies have already proposed the mechanisms involved and potential interventions. Interestingly, emerging data highlighted that LKB1 alterations represent positive determinants to the new KRAS specific inhibitors response in KRAS co-mutated NSCLCs. In conclusion, the absence of the target did not block the development of treatments able to hit LKB1-mutated NSCLCs acting on several fronts. This will give patients a concrete chance to finally benefit from an effective therapy.

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“…Consequently, the elevated AMP/ATP ratio activates adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which promotes cell cycle arrest and inhibits tumor cell proliferation (11). Recently, it has been demonstrated that clinical doses of metformin-bound PEN2 forms a complex with ATP6AP1, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels (12). Preclinical studies and retrospective population-based studies have suggested antitumor activity of metformin alone or in combination with conventional anticancer drugs (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8⁺ T cells

Chen

et al. 2022

Preprint

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Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, which limits the selectivity of prevention and treatment. Preclinical and clinical studies suggested that in patients with diabetes, prolonged use of metformin, the AMPK activator, was associated with a reduction of HCC incidence. This association promotes us to investigate the possible functions and mechanisms of metformin in HCC without diabetes backgrounds. Here, we found that several unique pathways that changed during chronic liver injury of Fah-/- mice, including glucose metabolic process and retinol metabolism. Further, metformin suppressed the tumor formation in chronic liver injury of Fah-/- mice. RNA sequencing, in vivo and in vitro experiments showed that metformin suppressed Cyp26a1 gene expression of hepatocyte. Moreover, the down-regulation of Cyp26a1 leads to the increased level of all-trans-retinoic acid (atRA), which could suppress the tumor formation in our model. On the other hand, flow multicolor analysis showed that the cell number and proportion of cancer promoting (pro-tumor) CD8+ T cells increased significantly during chronic liver injury in Fah-/- mice, and both metformin and atRA treatment could reduce the number and proportion of pro-tumor CD8+ T cells. We also found metformin decreased the Cyp26a1 expression through the AMPK/JNK/c-Jun pathway. In short, the association between the metformin and atRA may explain the commonness of their anti-tumor activities. Our findings highlight the importance of targeting the precancerous microenvironment for the prognosis, prevention and treatment of HCC.

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Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Cited by 225 publications

References 69 publications

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

LKB1: Can We Target an Hidden Target? Focus on NSCLC

Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8⁺ T cells

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Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Cited by 225 publications

References 69 publications

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming

LKB1: Can We Target an Hidden Target? Focus on NSCLC

Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8+ T cells

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Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8⁺ T cells