Role of GSK-3β in Regulation of Canonical Wnt/β-catenin Signaling and PI3-K/Akt Oncogenic Pathway in Colon Cancer

Jain, Shelly; Ghanghas, Preety; Rana, Chandan; Sanyal, Sankar Nath

doi:10.1080/07357907.2017.1337783

Cited by 38 publications

(31 citation statements)

References 36 publications

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“…The activation of AKT/mTOR involves phosphorylation of AKT and mTOR. Interestingly, studies have shown that activated AKT could result in phosphorylation and inactivation of GSK3β [13,14], which therefore promotes β-catenin accumulation and nuclear translocation in Wnt/β-catenin pathway [15]. These previous findings indicate the crosstalk between AKT/mTOR and Wnt/β-catenin signaling pathways, and the regulation of these two pathways has also been reported in several cancers [16,17].…”

Section: Introductionmentioning

confidence: 75%

“…Former studies have delineated that AKT/mTOR pathway and Wnt/β-catenin pathway are key pattern regulating cancer progression [12,26], including in cervical cancer [18,19]. Also, several studies have revealed the crosstalk of these two pathways by demonstrating that p-AKT could induce the phosphorylation GSK3β so as to inhibit GSK3β [13,14], which consequently leads to β-catenin accumulation and nuclear migration, thus activating Wnt/β-catenin pathway [15]. Our study first related GHET1 to AKT/mTOR and Wnt/β-catenin pathways in CC by showing that down-regulating GHET1 reduced the activities of AKT/mTOR pathway and Wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Results of Western blot showed that down-regulating GHET1 reduced expression of p-AKT and p-mTOR in HeLa and SiHa cells, but had no effect on total AKT and mTOR (Figure 2A), indicating that GHET1 positively regulated AKT/mTOR pathway. Moreover, it has been proved that p-AKT could induce the phosphorylation GSK3β [13,14], which therefore leads to acumulation and nuclear migration of β-catenin [15]. Hence, we probed effects of GHET1 on Wnt/β-catenin pathway.…”

Section: Knockdown Of Ghet1 Suppressed Akt/mtor and Wnt/β-catenin Patmentioning

confidence: 98%

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LncRNA GHET1 promotes cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways

Liu

Luo

et al. 2020

Bioscience Reports

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Cervical cancer (CC) is a prevalent gynecological cancer, and the patients with CC usually suffer from dismal prognosis. Long non-coding RNAs (lncRNAs) are demonstrated to serve as promising biological targets in human cancers. Gastric carcinoma proliferation enhancing transcript 1 (GHET1) has been revealed to function as an oncogene in several cancers, but it has never been investigated in CC. We proposed to examine the biological role of GHET1 in CC and the underlying mechanism and validated the up-regulated expression of GHET1 in CC cell lines. Loss-of-function assays demonstrated that down-regulation of GHET1 inhibited cell growth, migration and epithelial-to-mesenchymal transition (EMT) in CC. Furthermore, we validated that GHET1 down-regulation could inactivate AKT/mTOR and Wnt/β-catenin pathways, and that respective activation of these two pathways abrogated the inhibitive effect of GHET1 knockdown on CC cell growth, migration and EMT. Moreover, we unfolded a preliminary investigation on the modulation of GHET1 on AKT/mTOR and Wnt/β-catenin pathways. We found that GHET1 stabilized E2F6 mRNA through interacting with IGF2BP2, so as to regulate the activity of AKT/mTOR and Wnt/β-catenin pathways. Rescue assays also proved that GHET1 regulated these two pathways and CC cell growth, migration and EMT through E2F6. In conclusion, we revealed that down-regulation of GHET1 suppresses cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways, indicating GHET1 as a promising molecular biomarker for CC treatment improvement.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of Ghet1 Suppressed Akt/mtor and Wnt/β-catenin Patmentioning

confidence: 98%

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LncRNA GHET1 promotes cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways

Liu

Luo

et al. 2020

Bioscience Reports

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“…Different components and targets of the Wnt canonical pathway were evaluated by RT-qPCR. It was shown that Akt may inhibit GSK3β, which is a repressor of β-Catenin transcription factor [30]. GSK3β mRNA expression presented an expected opposite pattern of expression compared to β-Catenin (CTNNB1) mRNA.…”

Section: Emt: Wnt Canonical Pathwaymentioning

confidence: 99%

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

et al. 2020

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Background Alpha-1-antitrypsin is a protein involved in avoidance of different processes that are seen in diabetic retinopathy pathogenesis. These processes include apoptosis, extracellular matrix remodeling and damage of vessel walls and capillaries. Furthermore, because of its antiinflammatory effects, alpha-1-antitrypsin has been proposed as a possible therapeutic approach for diabetic retinopathy. Our group tested alpha-1-antitrypsin in a type 1 diabetes mouse model and observed a reduction of inflammation and retinal neurodegeneration. Thus, shedding light on the mechanism of action of alpha-1-antitrypsin at molecular level may explain how it works in the diabetic retinopathy context and show its potential for use in other retinal diseases. Methods In this work, we evaluated alpha-1-antitrypsin in an ARPE-19 human cell line exposed to high glucose. We explored the expression of different mediators on signaling pathways related to pro-inflammatory cytokines production, glucose metabolism, epithelial-mesenchymal transition and other proteins involved in the normal function of retinal pigment epithelium by RT-qPCR and Western Blot. Results We obtained different expression patterns for evaluated mediators altered with high glucose exposure and corrected with the use of alpha-1-antitrypsin.

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“…Recently, the biological effects of small molecule compounds on GSK-3β were widely studied for its potential value on CRC treatment. It is reported that activation of GSK-3β while downregulating the PI3-K/Akt oncogenic pathway by non-steroidal anti-inflammatory drugs (NSAIDs), results uniformly in the chemopreventive and anti-neoplastic effects in the early stage of colon cancer (45). In the present study, treated with BIO in CRC cells, the expression levels of p-GSK-3β (Tyr 216) were decreased both in CRC SW480 and SW620 cells, demonstrating that GSK-3β activity was significantly inhibited by BIO.…”

Section: Discussionmentioning

confidence: 99%

GSK-3β inhibitor 6-bromo-indirubin-3′-oxime promotes both adhesive activity and drug resistance in colorectal cancer cells

Liu

et al. 2017

International Journal of Oncology

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Multi-targets inhibitor 6-bromo-indirubin-3'-oxime (BIO) has diverse biological effects on cancer cells. The key component of the β-catenin destruction complex glycogen synthase kinase 3β (GSK-3β), one of the major target for BIO, polyubiquitination and degradation of the main oncoprotein β-catenin in colorectal cancer (CRC). In the present study, we evaluated the effect of BIO on drug resistance and biological properties of CRC cells. Whole-genome transcriptional profiling revealed that differentially expressed genes were mainly centered on well-characterized signaling pathways including stem cell, cell adhesion and cell growth in BIO-treated CRC cells. BIO treatment downregulated migration and invasion abilities of CRC cells, accompanying with MMP-9 downregulated and E-cadherin upregulated CRC cells. BIO treatment decreased apoptosis induced by 5-Fu/DDP in CRC SW480 cells. In addition, BIO treatment reversed the 5-Fu-induced CD133+ cell downregulation trend in CRC SW620 cells. After incubation with BIO, the expression levels of EpCAM, TERT and DCAMKL-1 proteins were upregulated in CRC cells. BIO treatment downregulated the activity of GSK-3β, upregulated and transported β-catenin to the nucleus in CRC cells. Our findings reveal that BIO treatment upregulated stemness, adhesive and chemoresistance of CRC cells. GSK-3β inhibition and WNT/β-catenin activation by BIO, may partly result in the biological behavior alterations in CRC cells.

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Role of GSK-3β in Regulation of Canonical Wnt/β-catenin Signaling and PI3-K/Akt Oncogenic Pathway in Colon Cancer

Cited by 38 publications

References 36 publications

LncRNA GHET1 promotes cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways

LncRNA GHET1 promotes cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

GSK-3β inhibitor 6-bromo-indirubin-3′-oxime promotes both adhesive activity and drug resistance in colorectal cancer cells

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