Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

Zhu, Zhongling; Jiang, Teng; Suo, Huirong; Xu, Shan; Zhang, Cai; Ying, Guoguang; Zhao, Yan

doi:10.3389/fphar.2021.712181

Cited by 11 publications

(11 citation statements)

References 43 publications

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“…For example, activating AMPK-mTOR-ULK1 reinforced autophagy, apoptosis, and cytotoxicity in human bladder cancer induced by10-hydroxycamptothecin [45]. The AMPK-mTOR axis took part in NSCLC treatment by inhibiting cell proliferation, migration, invasion, and glycolysis and activating oxidative stress, autophagy, and apoptosis [46][47][48][49]. In the present study, RSV activated AMPK and mTOR by phosphorylation.…”

Section: Discussionsupporting

confidence: 50%

“…The impacts of RSV on the cell viability of human lung adenocarcinoma A549 cells and human bronchial epithelial BEAS-2B cells were evaluated by MTT assay. Two cell lines were treated with corresponding RSV concentrations (0, 5, 10, 20, 40, 60, 80, 100, 120, 140, 160, 180, and 200 µM) and duration (12,24,48, and 72 h) to select the appropriate treatment conditions. The results showed that lower concentration (5-20 µM) or shorter duration (12 h) of RSV treatment promoted cell viability of both A549 and BEAS-2B cells, compared with the control group.…”

Section: The Effect Of Rsv On Cell Viability In A549 and Beas-2b Cellsmentioning

confidence: 99%

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Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

Fan

Zhang

et al. 2022

Nutrients

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Resveratrol (RSV) has been reported to induce autophagy and apoptosis in non-small-cell lung cancer A549 cells, and the nerve growth factor receptor (NGFR) regulates autophagy and apoptosis in many other cells. However, the effect of NGFR on autophagy and apoptosis induced by RSV in A549 cells remains unclear. Here, we found that RSV reduced the cell survival rate in time- and concentration-dependent manners, activating autophagy and apoptosis. Lethal autophagy was triggered by RSV higher than 55 μM. The relationship between autophagy and apoptosis depended on the type of autophagy. Specifically, mutual promotion was observed between apoptosis and lethal autophagy. Conversely, cytoprotective autophagy facilitated apoptosis but was unaffected by apoptosis. RSV enhanced NGFR by increasing mRNA expression and prolonging the lifespan of NGFR mRNA and proteins. RSV antagonized the enhanced autophagy and apoptosis caused by NGFR knockdown. As the downstream pathway of NGFR, AMPK-mTOR played a positive role in RSV-induced autophagy and apoptosis. Overall, RSV-induced autophagy and apoptosis in A549 cells are regulated by the NGFR-AMPK-mTOR signaling pathway.

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Section: Discussionsupporting

confidence: 50%

Section: The Effect Of Rsv On Cell Viability In A549 and Beas-2b Cellsmentioning

confidence: 99%

Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

Fan

Zhang

et al. 2022

Nutrients

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“…Pro-inflammatory factors and immune-related factors also play different roles in the process of tumor metastasis. For example, mitochondrial reactive oxygen species (ROS) can further affect tumor metastasis by regulating the inflammatory response [ 39 – 41 ]. Thus some natural antioxidants or anti-inflammatory drugs may also be used to inhibit tumor metastasis [ 39 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, mitochondrial reactive oxygen species (ROS) can further affect tumor metastasis by regulating the inflammatory response [ 39 – 41 ]. Thus some natural antioxidants or anti-inflammatory drugs may also be used to inhibit tumor metastasis [ 39 , 42 , 43 ]. In colorectal cancer, including the spectrum from normal colorectal adenoma to cancer, infiltrating macrophages display high levels of Wnt2 and Wnt5a.…”

Section: Discussionmentioning

confidence: 99%

Wnt pathway-related three-mRNA clinical outcome signature in bladder urothelial carcinoma: computational biology and experimental analyses

Sun

Wang

et al. 2021

J Transl Med

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Background The Wnt signaling pathway is core to the growth of bladder tumors. Epithelial-to-mesenchymal transition (EMT) is significant for bladder tumor metastasis. Nevertheless, the relationship between the Wnt signaling pathway, outcomes of bladder cancer (BLCA), and the specific mechanisms driving immune infiltration have not been studied. Methods We obtained Wnt pathway-related gene mRNA and clinicopathological data from the Cancer Genome Atlas (TCGA). We obtained 34 genes that were greatly correlated with outcome using univariate Cox regression analysis and conducted a completely randomized data t-test to perform clinical staging. According to the single-sample gene set enrichment analysis (ssGSEA), the weighted correlation network analysis (WGCNA) was applied to identify relevant biological functions. Various subtypes were identified using consensus cluster analysis. Univariate Cox regression and least absolute shrinkage sum selection operator–Cox regression algorithm analysis were conducted on TCGA and Gene Expression Omnibus data to identify risk characteristics. The Kaplan–Meier method and receiver running feature curves were adopted to calculate overall survival. Single-sample gene set enrichment analysis (ssGSEA) was adopted for the assessment of the degree of immune infiltration. Then, we demonstrated the relationship between PPP2CB and EMT function in two cell lines. Results Thirty-four Wnt signaling pathway-related genes were risk factors for BLCA outcome, and their expression levels differed by clinical stage. The co-expression of WGCNA showed the relationship between the Wnt signaling pathway and biological functions and was closely associated with EMT. We divided BLCA patients into two subtypes using consensus clustering. Survival curves and clinical analysis showed that the Wnt pathway enriched group had worse outcomes. The Wnt signature showed the significance of the outcome for MAPK10, PPP2CB, and RAC3. Based on these genes, the degree of immune infiltration was evaluated. Cell function experiments suggested that PPP2CB drives the proliferation and migration of BLCA cells. Conclusion We found that Wnt signaling pathway-related genes can be used as prognostic risk factors for BLCA, and the Wnt signaling pathway is a cancer-promoting signaling pathway associated with EMT. We identified three critical genes: MAPK10, RAC3, and PPP2CB. The genes in these three Wnt signaling pathways are associated with tumor cell EMT and immune cell infiltration. The most important finding was that these three genes were independent prognostic factors for BLCA.

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“…Various preclinical studies have indicated that metformin can suppress cell proliferation, trigger apoptotic cell death, provoke cell cycle arrest in vitro , and diminish the occurrence and growth of tumors in an in vivo orthotopic or xenograft mouse model system ( Buzzai et al ., 2007 ; Ben Sahra et al ., 2008 ; Zhao et al ., 2015 ; Zi et al ., 2015 ). Metformin can be used as a sensitizer or can be combined with standard chemo-therapeutic agents and radiotherapy to treat tumors ( Fasih et al ., 2014 ; Qu et al ., 2014 ; Zhang et al ., 2014 ; Lengyel et al ., 2015 ; Uehara et al ., 2015 ; Zhu et al ., 2021 ). Furthermore, metformin plays an important role in targeting tumor stem cells and in reverting the epithelial-mesenchymal transition, a key process in tumor metastasis ( Barriere et al ., 2013 ; Nangia-Makker et al ., 2014 ; Lei et al ., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Rho

Byun

Kim

et al. 2021

Biomol Ther (Seoul)

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Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphateactivated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.

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Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

Cited by 11 publications

References 43 publications

Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

Wnt pathway-related three-mRNA clinical outcome signature in bladder urothelial carcinoma: computational biology and experimental analyses

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

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