Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells

Saladini, Serena; Aventaggiato, Michele; Barreca, Federica; Morgante, Emanuela; Sansone, Luigi; Russo, Matteo Antonio; Tafani, Marco

doi:10.3390/cells8010049

Cited by 31 publications

(35 citation statements)

References 60 publications

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“…In addition, metformin has been reported to inhibit epithelial-to-mesenchymal transition (EMT) to suppress tumor progression [10]. Other than the above molecular mechanisms, metformin is also involved in tumor cells autophagy [7,8], apoptosis [9], epigenetic features [6] and immune responses [13,14]. In general, relative few reports focus on the effects of metformin on tumor metastasis and most molecular mechanisms about metformin are involved in intracellular signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Some exciting reports show that metformin inhibits tumor progression alone or in combination with other drugs [2][3][4][5]. Varied mechanisms underlying the anti-tumor effect of metformin have been demonstrated in a number of studies [6][7][8][9][10][11][12][13][14]. Metformin can cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, such as miR-192-5p, miR-584-3p, miR-1246, EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene and secretory carrier membrane proteins (SCAMP3) gene [6].…”

Section: Introductionmentioning

confidence: 99%

“…Metformin can cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, such as miR-192-5p, miR-584-3p, miR-1246, EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene and secretory carrier membrane proteins (SCAMP3) gene [6]. Many studies report that metformin can suppress the growth of tumor by leading to apoptosis and autophagy [7][8][9]. Several studies also show that metformin can inhibit the epithelial to mesenchymal transition (EMT) process [10][11][12] and regulate the immune system to suppress tumor progression [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Gong

Wang

Jiang

et al. 2020

Cells

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Metformin has been documented in epidemiological studies to mitigate tumor progression. Previous reports show that metformin inhibits tumor migration in several cell lines, such as MCF-7 and H1299, but the mechanisms whereby metformin exerts its inhibitory effects on tumor metastasis remain largely unknown. The secreted proteins in cancer cell-derived secretome have been reported to play important roles in tumor metastasis, but whether metformin has an effect on tumor secretome remains unclear. Here we show that metformin inhibits tumor metastasis by suppressing Hsp90α (heat shock protein 90α) secretion. Mass spectrometry (MS) analysis and functional validation identify that eHsp90α (extracellular Hsp90α) is one of the most important secreted proteins for metformin to inhibit tumor cells migration, invasion and metastasis both in vitro and in vivo. Moreover, we find that metformin inhibits Hsp90α secretion in an AMPKα1 dependent manner. Our data elucidate that AMPKα1 (AMP-activated protein kinase α1) decreases the phosphorylation level of Hsp90α by inhibiting the kinase activity of PKCγ (protein kinase Cγ), which suppresses the membrane translocation and secretion of Hsp90α. Collectively, our results illuminate that metformin inhibits tumor metastasis by suppressing Hsp90α secretion in an AMPKα1 dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Gong

Wang

Jiang

et al. 2020

Cells

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“…[ 14 ] A large number of interventional and molecular studies have demonstrated that metformin has anti-tumor properties, [ 11 , 15 , 16 ] but the possible mechanisms underlying the properties remain unknown. In the past, metformin has been proven to inhibit GLS (glutaminase) activity and ammonia accumulation, [ 17 ] thereby reducing the risk of some diseases in patients with type 2 diabetes mellitus. Since tumor cells are highly glutamine dependent and overexpress glutaminase, the mechanism of tumor suppression of metformin could be due to inhibition of GLS and the reduction of ammonia and ammonia-induced autophagy.…”

Section: Discussionmentioning

confidence: 99%

Melanotic neuroectodermal tumor of infancy successfully treated with metformin

Tian²,

Wang³

et al. 2020

Medicine

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Rationale: Melanotic neuroectodermal tumor of infancy (MNTI) is a rare tumor originated from neural crest cells with the potential for recurrence and metastasis. The peak age for the disease is during the first year after birth. The current therapy is primarily surgery. The patient reported here is the first case of MNTI treated with metformin. Patient concerns: A case of a 4-month-old infant with a history of swelling in the mouth for 1 month. Diagnosis: The tumor was diagnosed using radiology, pathology, and immunohistochemistry, and it was performed with complete surgical resection. Unfortunately, the tumor recurred 3 months after surgery. Interventions: We prescribed metformin for the infant. Outcomes: Currently, after 9 months of treatment, the tumor is well controlled without apparent side effects. Lessons: The case presented suggested that metformin may be an underlying therapy for MNTI.

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“…NLRP3 inflammasomes, mainly expressed in microglia, have been reported to be regulated by various pathways, among which iNOS is a key activator 17 . Furthermore, exosome has been acknowledged as an inducer of autophagy 18 .Previous study reveals that autophagy deficiency contributes to ROS accumulation 19 and exacerbation of neuroinflammation 20,21 induced by exosome. However, the role of exosome-enhanced autophagy in NLRP3 activation remains obscure.…”

Section: Introductionmentioning

confidence: 99%

Exosome derived from mesenchymal stem cells enhance autophagy and inhibit iNOS/TXNIP/NLRP3 inflammasome axis in injured spinal cord

Wang

Huang

et al. 2020

Preprint

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Background: Neuroinflammation, autophagy, NLRP3 inflammasome, and microglia polarizationhave been implicated in spinal cord injury (SCI).Moreover, exosomes, a classic nanovesicles secreted by MSCs, may have a neuroprotective effect on transformation of microglia from the M1 state to the M2 phenotype. However, the effect of MSCs derived exosomes on neuroinflammation is still unclear. Here, we investigated the mechanisms of MSCs derived exosomes mediated NLRP3 inflammasome signaling cascades and its protective effects in SCI. Methods:The SCI model was performed by weight-drop impact in adult male Sprague-Dawley (SD) rats. Control andexosome rats were randomly subjecttoexosomeadminister (20 mg/kg) or placebo via intraperitoneal route 1 h after SCI.Autophagy inhibitor(3-MA) was administered intraperitoneally 20 min before experiment.Neurological function was measured by Basso-Beattie-Bresnahan (BBB) scoring and an open-field test.Neuronal death was measured by HE stainingandNisslstaining.Inducible nitric oxide synthase (iNOS) levels were determined using fluorescent probes. The autophagy and TXNIP and its downstream signaling pathways-mediated polarization of macrophages/microglia was assessed by immunohistochemistry. Results:Exosome significantly downregulated intracellular iNOS and inhibited TXNIP, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation by activating autophagy. Additionally, Exosomepromoted expression of autophagy markers, such as LC3A/B and beclin1,and abrogated the expression of p62. Autophagy inhibitor, 3-MA, blockage of autophagy flux abolished the inhibition of apoptosis and iNOS/TXNIP/NLRP3 inflammasome axisafterSCI. Here, we demonstrated that exosomeadministration in spinal cord markedly reduced tissue loss, attenuate pathological morphology of the injuredregion, and promoted tissue recovery. Moreover. our resultshowed that exosome administration alleviated neuronal cells apoptosis, and inhibited nitric oxide release in microglia.The activation of inflammatoryresponse in neuronal cells facilitates interactions of iNOS‐NLRP3 andTXNIP‐NLRP3and inhibited NLRP3 inflammasome where neuronal cells apoptosis was induced.Further, we found that exosome could suppress macrophages/microglia polarized to M1 phenotype in vivo and in vitro.Taken together, exosome administration exerts protective effects in neuronal cells through inhibiting iNOS production, and exosome administration could inhibit iNOS/TXNIP/NLRP3 inflammasome axis via enhancing autophagy and both in vitro and in vivo. Conclusions:These resultsreveal that exosometreatment alleviatedneuroinflammation and mitigates neuronal apoptosis via autophagy-mediate inhibition of the iNOS/TXNIP/NLRP3 inflammasome axis. Our findings suggest that exosome may be a novel therapeutic target for treating SCI.

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Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells

Cited by 31 publications

References 60 publications

Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Melanotic neuroectodermal tumor of infancy successfully treated with metformin

Exosome derived from mesenchymal stem cells enhance autophagy and inhibit iNOS/TXNIP/NLRP3 inflammasome axis in injured spinal cord

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