Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

Singh, Supriya; Yap, Wei Ney; Arfuso, Frank; Kar, Shreya; Wang, Chao; Cai, Wanpei; Dharmarajan, Arun; Sethi, Gautam; Kumar, Alan Prem

doi:10.3748/wjg.v21.i43.12261

Cited by 148 publications

(103 citation statements)

References 112 publications

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“…Molecular alterations of this pathway have been widely reported in cancers, which mainly include phosphorylation of PI3K and/or AKT . These molecules in the PI3K/AKT pathway regulate various physiological functions, including cell survival, proliferation, migration, invasion and protein translation . In the present study we found that the levels of p‐PI3K and p‐AKT were markedly reduced after KYNU was silenced.…”

Section: Discussionsupporting

confidence: 60%

“…17 These molecules in the PI3K/AKT pathway regulate various physiological functions, including cell survival, proliferation, migration, invasion and protein translation. 20,21 In the present study we found that the levels of p-PI3K and p-AKT were markedly reduced after KYNU was silenced. We therefore suggest that KYNU possibly acts as a promoter in the growth and motility of cSCC cells, at least partially by activating the PI3K/AKT pathway.…”

Section: Discussionsupporting

confidence: 56%

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Downregulation of kynureninase restrains cutaneous squamous cell carcinoma proliferation and represses the PI3K/AKT pathway

Lyu

et al. 2019

Clin Exp Dermatol

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Summary Background The protein kynureninase (KYNU) has recently been reported to participate in the pathological processes of various diseases. Aim To explore the expression and the biological function of KYNU in cutaneous squamous cell carcinoma (cSCC). Methods Expression of KYNU in cSCC cell lines and tissues was firstly evaluated based on the Gene Expression Omnibus and the Oncomine databases. Quantitative reverse transcription–PCR was performed to determine the mRNA expression of KYNU in cSCC cell lines. Small interfering RNA (siRNA) was used for silencing KYNU. The effect of KYNU on the growth and motility of cSCC cells was determined by cell counting kit‐8, wound‐healing and Transwell assays, and western blotting was used to determine the protein expression of KYNU, AKT, phosphoinositide 3‐kinase (PI3K), phosphorylated (p)‐AKT and p‐PI3K. Results KYNU was significantly upregulated in cSCC tissues and cell lines. Knockdown of KYNU using siRNA noticeably suppressed the proliferation, migration and invasion ability of SCL‐1 cells (P < 0.01). Western blotting revealed that phosphorylation of AKT and PI3K was markedly inhibited after silencing KYNU. The ratios of p‐AKT/AKT and p‐PI3K/PI3K were significantly decreased in the si‐KYNU group compared with the control group. Conclusion Depletion of KYNU could inhibit the growth of cSCC cells, possibly through modulating PI3K/AKT pathway. These data indicate that KYNU takes a key part in the malignant progression of cSCC, and could be considered as a promising therapeutic target for cSCC treatment.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 56%

Downregulation of kynureninase restrains cutaneous squamous cell carcinoma proliferation and represses the PI3K/AKT pathway

Lyu

et al. 2019

Clin Exp Dermatol

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“…demonstrated that RES reversed MDR in human breast cancer doxorubicin‐resistant cells . In the present study, we validated the assumption that RES reversed DOX resistance in breast neoplasm through inhibiting PI3K/Akt/mTOR signaling pathway, in which PI3K phosphorylated Akt, then Akt stimulated mTOR, and thus resulted in ribosomal S6 kinase (p70S6K) phosphorylation . On the other hand, the down‐regulation of caspase‐3 and inactivation of caspase‐based apoptosis was measured by western blotting and Flow Cytometry Method (FCM).…”

Section: Discussionsupporting

confidence: 76%

Effect of resveratrol on doxorubicin resistance in breast neoplasm cells by modulating PI3K/Akt signaling pathway

2018

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In the study, we probed into the effect of Resveratrol (RES) on Doxorubicin (DOX)-resistant breast neoplasm cell line MCF-7/DOX as well as the mechanism of RES underlying the DOX-resistant breast cancer. CCK-8 assay was utilized to assess the survival rates and sensitivity of breast neoplasm cell lines MCF-7 or MDA-MB-231 to DOX and RES. DOX-resistant MCF-7 cell line was successfully cultivated with DOX dose increasing and was named MCF-7/DOX. Afterwards, wound healing and Transwell assays were performed to measure the migration and invasion capabilities of MCF-7/DOX cells, while cell propagation and apoptosis were determined by colony formation assay and flow cytometry analysis. Both western blotting and immunohistochemistry were conducted to examine the expression of proteins involved in PI3K/Akt signaling pathway. Nude mice xenograft model was constructed to further verify the effects of DOX and RES on breast neoplasm in vivo. RES restored DOX sensitivity in MCF-7/DOX cells, inhibiting biological functions of MCF-7/DOX cells and promoting cell apoptosis in vitro and impeding tumor growth in vivo. It was revealed by the mechanistic studies that MCF-7/DOX cells could regain the drug sensibility with RES treatment through inactivating the PI3K/Akt signal transduction pathway. RES could reverse DOX resistance in breast neoplasm cells and inhibited DOX-resistant breast cancer cell propagation and metastasis and facilitated cell apoptosis by modulating PI3K/Akt signaling pathway. © 2018 IUBMB Life, 70(6):491-500, 2018.

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“…Several signaling pathways, including the wnt/β-catenin, Notch, and PI3K/Akt pathways, have been found to be aberrantly activated and play vital roles in the development and progression of gastric cancer [11, 30, 31] Among these pathways, the functions of wnt/β-catenin signaling in gastric cancer development and progression have been well documented. TCF4 and coactivator β-catenin are two key downstream effectors of the wnt/β-catenin signaling pathway, and considered as potent oncogenes in tumor progression [7].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer

Fan

Ren

Yang

et al. 2016

J Exp Clin Cancer Res

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BackgroundmiRNAs are critical post-transcriptional regulators of gene expression and key mediators of tumourigenesis. miR-501-5p is newly identified to be involved in the tumor progression, but its biological role and mechanism remain largely unknown. This study is aimed to study the role of miR-501-5p in the progression of gastric cancer.MethodsReal-time PCR analysis was used to determine miR-501-5p expression in gastric cancer cell lines, clinical tissues and 112 clinicopathologically characterized gastric cancer specimens. The role of miR-501-5p in maintaining gastric cancer stem cell like phenotype was examined by tumor-sphere formation assay and expression of stem cell markers. Luciferase reporter assay, cellular fractionation and western blot analysis were used to determined that miR-501-5p activated the wnt/β-catenin signaling by directly targeting DKK1, NKD1 and GSK3β.ResultsHerein, our results revealed that miR-501-5p was markedly upregulated in gastric cancer cell lines and clinical tissues. High miR-501-5p levels predicted poor overall survival in gastric cancer patients. Gain-of-function and loss-of-function studies showed that ectopic expression of miR-501-5p enhanced the cancer stem cell-like phenotype in gastric cancer cells. Notably,wnt/β-catenin signaling was hyperactivated in gastric cancer cells that overexpress miR-501-5p, and mediated miR-501-5p-induced cancer stem cell-like phenotype. Furthermore, miR-501-5p directly targeted and suppressed multiple repressors of the wnt/β-catenin signaling cascade, including DKK1, NKD1 and GSK3β. These results demonstrate that miR-501-5p maintains constitutively activated wnt/β-catenin signaling by directly targeting DKK1, NKD1 and GSK3β, which promotes gastric cancer stem cell like phenotype.ConclusionsTaken together, our findings reveal a new regulatory mechanism of miR-501-5p and suggest that miR-501-5p might be a potential target in gastric cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0432-x) contains supplementary material, which is available to authorized users.

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Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

Cited by 148 publications

References 112 publications

Downregulation of kynureninase restrains cutaneous squamous cell carcinoma proliferation and represses the PI3K/AKT pathway

Downregulation of kynureninase restrains cutaneous squamous cell carcinoma proliferation and represses the PI3K/AKT pathway

Effect of resveratrol on doxorubicin resistance in breast neoplasm cells by modulating PI3K/Akt signaling pathway

Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer

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