Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway

El-Ashmawy, Nahla E.; El-Zamarany, Enas A.; Khedr, Eman G.; Abo-Saif, Mariam A.

doi:10.1007/s11010-019-03514-x

Cited by 32 publications

(21 citation statements)

References 28 publications

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“…Akt/mTOR, Stat3, and NF-κB signalling pathways play an important role in cell proliferation and migration. [29][30][31] ALO treatment caused a marked decrease in the activation of the Akt/mTOR/P70S6K and Stat3 signalling pathways. Furthermore, IκBα phosphorylation was also considerably reduced ( Figure 4).…”

Section: Discussionmentioning

confidence: 98%

“…However, IκB phosphorylation leads to its degradation, and the free p50 and p65 then translocate to the nucleus where they activate NF-κB-dependent gene transcription. 31 Therefore, we tracked the nuclear translocation of p65 upon ALO treatment of GC cells. As shown in Figure 5, p65 nuclear levels were found to significantly decrease following ALO treatment.…”

Section: Discussionmentioning

confidence: 99%

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<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Wang¹,

Tang²,

Wang³

et al. 2020

DDDT

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Background: Aloin has been reported to have many pharmacological effects including antiinflammatory, anti-oxidant and anti-tumour activities. However, the precise molecular mechanisms underlying the anti-tumour properties of aloin are yet to be elucidated. Methods: HGC-27 and BGC-823 gastric cancer cells were treated with aloin. EdU and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. Western blotting was used to detect the levels of cyclinD1, cyclin E1, MMPs, N-cadherin, E-cadherin and NOX2. The phosphorylation of Akt, mTOR, P70S6K, S6, Src, stat3 and IκBα were also detected by Western blotting. Flow cytometry was used to detect the cell cycle distribution.The location of p65 in cells was determined by using a confocal microscopy assay. The total amounts of ROS present in cells were measured using an ROS assay kit. Results: Here, we found that aloin inhibited the proliferation and migration of HGC-27 and BGC-823 gastric cancer cells using a combination of EdU, colony formation, wound healing and transwell assays. Further investigations revealed that aloin decreased the protein expression levels of cyclin D1, N-cadherin, and the matrix metalloproteinases (MMP)-2 and MMP-9; increased E-cadherin expression in a dose-dependent manner; inhibited reactive oxygen species (ROS) generation; and mediated the activation of Akt-mTOR, signal transducer and activator of transcription-3 (Stat3), and NF-κB signalling pathways. Our results also indicated that aloin is able to attenuate the expression levels of the two regulatory proteins of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), p47 phox and p22 phox , but had no effect on the level of gp91 phox. N-acetylcysteine treatment of gastric cancer cells inhibited ROS production and Akt-mTOR, Stat3, and IκBα phosphorylation. Taken together, our data suggest that aloin inhibits the proliferation and migration of gastric cancer cells by downregulating NOX2-ROS-mediated activation of the Akt-mTOR, Stat3, and NF-κB signalling pathways. Conclusion: Our findings suggest a potential role for aloin in the prevention of gastric cancer cell proliferation and migration and provide novel insights into the anti-cancer properties of aloin.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Wang¹,

Tang²,

Wang³

et al. 2020

DDDT

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“…Additionally, MTDH has been found to be more highly expressed in primary tumor tissues than in normal tissues (Figure 3c). Moreover, previous studies have shown that MTDH can regulate the NF-κB pathway [34,35] and MTDH is induced by the TNF-α pathway [46]. Our previous study revealed that MDA-MB-231/IR cells show enhanced activity in the NF-κB pathway, the TNF signaling pathway, and the Toll-like receptor pathway [40].…”

Section: Discussionmentioning

confidence: 93%

“…We further identified the underlying mechanisms associated with the enrichment of the CSC population in MDA-MB-231/IR cells. It has been reported that MTDH plays a key role in cancer therapy resistance due to its ability to maintain CSC populations [14,31,35]. Elevated expressions of…”

Section: Discussionmentioning

confidence: 99%

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin

Nguyen

Moon

Ediriweera

et al. 2020

Cancers

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Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan–Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including β-catenin, CD44+, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.

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“…Thus, inhibiting NF-κB signaling has potential therapeutic applications in cancer. A previous study reported the activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway 11 . However, the role of MTDH/NF-κB p65 pathway is still unclear in OC.…”

Section: Introductionmentioning

confidence: 98%

The Effect of Metadherin on NF-κB Activation and Downstream Genes in Ovarian Cancer

et al. 2020

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Ovarian cancer (OC) is the most aggressive gynecological cancer. Even with the advances in detection and therapeutics, it still remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in OC. In this study, we found the MTDH is overexpressed in OC tissues. Through in vitro assays with overexpression cells, we characterized the role of MTDH. We confirmed MTDH stable overexpression significantly increased the expression of TNF-α, IL-6, IL-8, IL-10, and IL-1β. Interestingly, NF-kappa-B (NF-κB) and MTDH were found in a feed-forward loop motif. Thus, our findings support the notion that the MTDH and NF-κB signaling network contributes to OC traits. MTDH represents a new OC-associated gene that can contribute to insights of OC biology and suggests other treatment strategies.

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Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway

Cited by 32 publications

References 28 publications

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin

The Effect of Metadherin on NF-κB Activation and Downstream Genes in Ovarian Cancer

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