Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition

Zong, Huajie; Yin, Baobing; Zhou, Huading; Cai, Duan; Ma, Baojin; Xiang, Yang

doi:10.1007/s11033-014-3321-4

Cited by 72 publications

(59 citation statements)

References 16 publications

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“…In order to explore the roles of EMT-related proteins on metastasis when pCREB is diminished, we determined the expression of E-cadherin, which is one of epithelial markers supposed to be down-regulated during EMT. Vimentin, fibronection and N-cadherin, which are mesenchymal markers should be up-regulated during EMT [34]. Our results showed that DNCREB increased the expression of E-cadherin, in contrary, fibronection and N-cadherin was repressed in cells transfected with DNCREB.…”

Section: Pcreb-mediates Rcc Cell Metastasis Is Not Via Vimentinmentioning

confidence: 57%

Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer

Wang

Ren²,

Zhuang

et al. 2015

Expert Opinion on Therapeutic Targets

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Section: Pcreb-mediates Rcc Cell Metastasis Is Not Via Vimentinmentioning

confidence: 57%

Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer

Wang

Ren²,

Zhuang

et al. 2015

Expert Opinion on Therapeutic Targets

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“…For example NAC has been shown to inhibit mammalian target of rapamycin (mTOR; [59]), possibly by decreasing ROS and consequently inhibiting the positive feedback between mTOR and ROS [60]. As mTOR has been implicated in EMT [61, 62], it is a possibility that some of the changes induced by MMP-3-induced ROS could be associated with the mTOR pathway. This possibility is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

ROS-induced epithelial-mesenchymal transition in mammary epithelial cells is mediated by NF-κB-dependent activation of Snail

2014

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Epithelial-mesenchymal transition (EMT) is characterized by loss of cell-cell junctions, polarity and epithelial markers, and in turn, acquisition of mesenchymal features and motility. Changes associated with this developmental process have been extensively implicated in breast cancer progression and metastasis. Matrix metalloproteinases (MMPs) have been identified as specific inducers of EMT in mammary epithelial cells. MMP-3 induces EMT associated with malignant transformation via a pathway dependent upon production of reactive oxygen species (ROS). While the process by which exposure to MMP-3 leads to induction of ROS has been extensively studied, exactly how the MMP-3-induced ROS stimulate EMT remains unknown. Here, we used profiling methods to identify MMP-3-induced transcriptional alterations in mouse mammary epithelial cells, finding common overlap with changes mediated by nuclear factor-κB (NF-κB) and found in advanced breast cancer. In cultured cells, we found that Snail, an ROS-dependent key mediator of MMP-3-induced changes, is regulated by NF-κB in response to MMP-3. More specifically, we found MMP-3 to cause binding of p65 and cRel NF-κB subunits to the Snail promoter, leading to its transcription. Our results identify a specific pathway by which MMPs induce EMT and malignant characteristics, and provide insight into potential therapeutic approaches to target MMP-associated breast cancers.

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“…A study by Gulhati et al provided evidence of mTORC1/2 regulating epithelial–mesenchymal transition (EMT), motility, and metastasis in colorectal cancer [9]. Furthermore, Gupta et al and others demonstrated a role for mTORC2 specifically to positively regulate TGFβ signaling in cancer cell migration and invasion [8–10, 32, 33]. Thus, RICTOR amplification likely promotes increased cell motility in vitro via increased mTORC1/2 signaling.…”

Section: Discussionmentioning

confidence: 99%

RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR

et al. 2016

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Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells. In parallel, cells with RICTOR copy number (CN) gain showed increased sensitivity to three mTOR inhibitors, AZD8055, AZD2014 and INK128 in cell growth assays, with AZD2014 demonstrating the best inhibition of downstream signaling. SCLC cells with RICTOR CN gain also migrated more rapidly in chemotaxis and scratch wound assays and were again more sensitive to mTOR inhibitors. The overall survival in SCLC patients with RICTOR amplification was significantly decreased (p = 0.021). Taken together, our results suggest that SCLC patients with RICTOR amplification may constitute a clinically important subgroup because of their potential response to mTORC1/2 inhibitors.

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Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition

Cited by 72 publications

References 16 publications

Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer

Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer

ROS-induced epithelial-mesenchymal transition in mammary epithelial cells is mediated by NF-κB-dependent activation of Snail

RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR

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