Inactivation of Akt by arsenic trioxide induces cell death via mitochondrial-mediated apoptotic signaling in SGC-7901 human gastric cancer cells

Gao, Yanhui; Zhang, Haopeng; Yang, Shu-Meng; Yang, Yue; Ma, Yuyan; Zhang, Xinyu; Yang, Yanmei

doi:10.3892/or.2014.2994

Cited by 18 publications

(10 citation statements)

References 63 publications

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“…Furthermore, the NF-κB inhibitor SN50 leads to an increase in the effect of LY294002 on inducing death of human gastric carcinoma cells through upregulated expression of p53, PUMA, and Beclin1 [ 43 ]. Several factors have been reported to induce apoptosis via the PI3K/Akt pathway in gastric carcinoma [ 44 , 45 , 46 , 47 , 48 ]. Apoptosis of gastric carcinoma cells induced by isoalantolactone was associated with the dissipation of mitochondrial membrane potential due to downregulation of Bcl-2 and upregulation of Bax [ 49 ].…”

Section: The Role Of the Pi3k/akt/mtor Pathway In The Biological Pmentioning

confidence: 99%

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

Matsuoka

Yashiro

2014

Cancers

177

121

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The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations in the PI3K/Akt/mTOR pathway in gastric carcinoma have often been demonstrated. Many kinds of molecular targeting therapies are currently undergoing clinical testing in patients with solid tumors. However, with the exception of the ErbB2-targeting antibody, targeting agents, including PI3K/Akt/mTOR inhibitors, have not been approved for treatment of patients with gastric carcinoma. This review summarizes the current knowledge on PI3K/Akt/mTOR signaling in the pathogenesis of gastric carcinoma and the possible therapeutic targets for gastric carcinoma. Improved knowledge of the PI3K/Akt/mTOR pathway in gastric carcinoma will be useful in understanding the mechanisms of tumor development and for identifying ideal targets of anticancer therapy for gastric carcinoma.

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Section: The Role Of the Pi3k/akt/mtor Pathway In The Biological Pmentioning

confidence: 99%

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

Matsuoka

Yashiro

2014

Cancers

177

121

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“…A likely explanation for this phenomenon is the induction of ROS through arsenic toxicity, which in turn decreases AKT activity and promotes proapoptotic features. In human gastric cancer (SGC-7901) cell lines, ATO for up to 72 hours led to decreased phosphorylation at two AKT sites, Ser 473 and Thr308, although the protein levels stayed relatively same, indicating that arsenic can reduce activation of AKT rather than the total protein ( Gao et al, 2014 ). In another study led by Wang et al (2017) , arsenic disulfide has been found to inhibit the AKT/mTOR signaling pathway and induce autophagy and apoptosis in several osteosarcoma cell lines.…”

Section: Introductionmentioning

confidence: 99%

PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis

Chen

Costa

2018

Mol Pharmacol

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Arsenic is a naturally occurring, ubiquitous metalloid found in the Earth’s crust. In its inorganic form, arsenic is highly toxic and carcinogenic and is widely found across the globe and throughout the environment. As an International Agency for Research on Cancer–defined class 1 human carcinogen, arsenic can cause multiple human cancers, including liver, lung, urinary bladder, skin, kidney, and prostate. Mechanisms of arsenic-induced carcinogenesis remain elusive, and this review focuses specifically on the role of the PI3K/AKT/mTOR pathway in promoting cancer development. In addition to exerting potent carcinogenic responses, arsenic is also known for its therapeutic effects against acute promyelocytic leukemia. Current literature suggests that arsenic can achieve both therapeutic as well as carcinogenic effects, and this review serves to examine the paradoxical effects of arsenic, specifically through the PI3K/AKT/mTOR pathway. Furthermore, a comprehensive review of current literature reveals an imperative need for future studies to establish and pinpoint the exact conditions for which arsenic can, and through what mechanisms it is able to, differentially regulate the PI3K/AKT/mTOR pathway to maximize the therapeutic and minimize the carcinogenic properties of arsenic.

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“…In gastric cancer cells, ATO was reported to inhibit cellular proliferation and induce cell cycle arrest via modulation of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and p53 signaling [ 1 ]. The pro-apoptotic effect of ATO in gastric cancer cells is also suggested by inhibition of Akt and mTOR signaling [ 2 ]. A recent study showed that ATO may inhibit the signal transducer and activator of transcription 3 (STAT3) activation in alpha-fetoprotein-producing gastric cancer cells, and thereby induce apoptosis [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells

et al. 2018

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BackgroundWe investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process.MethodsWe used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route.ResultsTreatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate.ConclusionOur data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.

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Inactivation of Akt by arsenic trioxide induces cell death via mitochondrial-mediated apoptotic signaling in SGC-7901 human gastric cancer cells

Cited by 18 publications

References 63 publications

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis

Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells

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