Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells

Ge, Rongbin; Wang, Zongwei; Wu, Shulin; Zhuo, Yangjia; Otsetov, Aleksandar; Cai, Chao; Zhong, Weide; Wu, Chin‐Lee; Olumi, Aria F.

doi:10.18632/oncotarget.5023

Cited by 26 publications

(49 citation statements)

References 32 publications

(42 reference statements)

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“…Upregulation of mesenchymal cadherins promotes invasion and metastasis and enables metastatic cells to survive outside of the epithelial environment. Upregulation of N-and OB-cadherins correlates with higher Gleason patterns and promotes migration, metastasis and resistance to therapy [33][34][35][36][37][38][39][40][41][42]. Targeting of N-and OB-cadherin limits PCa growth, metastasis, castration resistance and angiogenesis [42][43][44].…”

Section: Introductionmentioning

confidence: 99%

T‐cadherin in prostate cancer: relationship with cancer progression, differentiation and drug resistance

Dasen

Vlajnic

Mengus

et al. 2016

The Journal of Pathology CR

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Prostate cancer represents the second leading cause of cancer‐related death in men. T‐cadherin (CDH13) is an atypical GPI‐anchored member of the cadherin family of adhesion molecules. Its gene was reported to be downregulated in a small series of prostate tumours. T‐cadherin protein expression/localisation in prostate tissue has never been investigated. The purpose of our study was to analyse CDH13 gene and protein levels in large sets of healthy and cancer prostate tissue specimens and evaluate CDH13 effects on the sensitivity of prostate cancer cells to chemotherapy. Analysis of CDH13 gene expression in the TCGA RNAseq dataset for prostate adenocarcinoma (N = 550) and in tissue samples (N = 101) by qPCR revealed weak positive correlation with the Gleason score in cancer and no difference between benign and malignant specimens. Immunohistochemical analysis of tissue sections (N = 12) and microarrays (N = 128 specimens) demonstrated the presence of CDH13 on the apical surface and at intercellular contacts of cytokeratin 8‐positive luminal cells and cells double‐positive for cytokeratin 8 and basal marker p63. T‐cadherin protein expression was markedly upregulated in cancer as compared to benign prostate hyperplasia, the increase being more prominent in organ‐confined than in advanced hormone‐resistant tumours, and correlated negatively with the Gleason pattern. T‐cadherin protein level correlated strongly with cytokeratin 8 and with an abnormal diffuse/membrane localisation pattern of p63. Ectopic expression of CDH13 in metastatic prostate cancer cell line DU145 reduced cell growth in the presence of doxorubicin. We conclude that CDH13 protein, but not its gene expression, is strongly upregulated in early prostate cancer, correlates with changes in luminal/basal differentiation and p63 localisation, and promotes sensitivity of cancer cells to doxorubicin. These data identify CDH13 as a novel molecule relevant for prostate cancer progression and response to therapy.

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Section: Introductionmentioning

confidence: 99%

T‐cadherin in prostate cancer: relationship with cancer progression, differentiation and drug resistance

Dasen

Vlajnic

Mengus

et al. 2016

The Journal of Pathology CR

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“…One study found that combination of metformin with other therapeutic agents, such as anti-AR agent bicalutamide, enhanced the growth inhibition of CRPC via AR-mediated signaling57. While metformin has been shown to inhibit NF-κB signaling in several other studies5859, the regulation of metformin to MUC1 signaling remains elusive60. In the current study, metformin alone had no significant effect on MUC1 expression; we reasoned that metformin sensitized the therapeutic effect of solamargine in prostate cancer cell growth partly through enhancing the inhibition of MUC1 expression.…”

Section: Discussionmentioning

confidence: 99%

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Xiang

Zhang

Tang

et al. 2016

Sci Rep

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Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.

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“…Decreasing N-cadherin expression can also be an AMPK-independent mode of metformin action in reversing or inhibiting EMT [ 225 ]. TGF-beta activated intracellular transcription factors Snail and Twist and cervical cancer EMT are also diminished after metformin [ 106 , 226 ].…”

Section: The Eis Regimen: Emt Triggers Maintenance Factors and 6 Cumentioning

confidence: 99%

Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen

Kast¹,

Skuli

Karpel‐Massler

et al. 2017

Oncotarget

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This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resisting, low proliferation, transient state that is an integral feature of cancers’ lethality generally and of glioblastoma specifically. It is believed to be during the EMT state that glioblastoma’s centrifugal migration occurs. EMT is also a feature of untreated glioblastoma but is enhanced by chemotherapy, by radiation and by surgical trauma. EIS Regimen uses the antifungal drug itraconazole to block Hedgehog signaling, the antidiabetes drug metformin to block AMP kinase (AMPK), the analgesic drug naproxen to block Rac1, the anti-fibrosis drug pirfenidone to block transforming growth factor-beta (TGF-beta), the psychiatric drug quetiapine to block receptor activator NFkB ligand (RANKL) and the antibiotic rifampin to block Wnt- all by their previously established ancillary attributes. All these systems have been identified as triggers of EMT and worthy targets to inhibit. The EIS Regimen drugs have a good safety profile when used individually. They are not expected to have any new side effects when combined. Further studies of the EIS Regimen are needed.

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Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells

Cited by 26 publications

References 32 publications

T‐cadherin in prostate cancer: relationship with cancer progression, differentiation and drug resistance

T‐cadherin in prostate cancer: relationship with cancer progression, differentiation and drug resistance

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen

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