The PI3-Kinase-Akt Pathway Promotes Mesangial Cell Survival and Inhibits Apoptosis In Vitro via NF-κB and Bad

Shimamura, Haruko; Terada, Yoshio; Okado, Tomokazu; Tanaka, Hiroyuki; Inoshita, Seiji; Sasaki, Sei

doi:10.1097/01.asn.0000066140.99610.32

Cited by 101 publications

(68 citation statements)

References 32 publications

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“…This assumption is based on the findings that PGE 2 receptors coupled to the GαS, and ligand binding has been reported to increase cyclic AMP levels leading to the activation of PKA and Akt (33). Akt and PKA activation can mediate prosurvival pathways through the inactivation of proapoptotic proteins (34,35). Our results are consistent with the report that PGE 2 protected gastric mucosal cells in vitro from ethanol-induced apoptosis via EP1 and EP4 activation (36).…”

Section: Discussionsupporting

confidence: 91%

Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors

Sharma

Meeran

Katiyar

2010

Molecular Cancer Therapeutics

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Overexpression of cyclooxygenase-2 (COX-2) and prostaglandins (PG) is linked to a wide variety of human cancers. Here, we assessed whether the chemotherapeutic effect of grape seed proanthocyanidins (GSP) on non-small cell lung cancer (NSCLC) cells is mediated through the inhibition of COX-2 and PGE 2 /PGE 2 receptor expression. The effects of GSPs on human NSCLC cell lines in terms of proliferation, apoptosis, and expression of COX-2, PGE 2 , and PGE 2 receptors were determined using Western blotting, fluorescence-activated cell sorting analysis, and reverse transcription-PCR. In vitro treatment of NSCLC cells (A549, H1299, H460, H226, and H157) with GSPs resulted in significant growth inhibition and induction of apoptosis, which were associated with the inhibitory effects of GSPs on the overexpression of COX-2, PGE 2 , and PGE 2 receptors (EP1 and EP4) in these cells. Treatment of cells with indomethacin, a pan-COX inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell growth and induced cell death. The effects of a GSP-supplemented AIN76A control diet fed to nude mice bearing tumor xenografts on the expression of COX-2, PGE 2 , and PGE 2 receptors in the xenografts were also evaluated. The growth-inhibitory effect of dietary GSPs (0.5%, w/w) on the NSCLC xenograft tumors was associated with the inhibition of COX-2, PGE 2 , and PGE 2 receptors (EP1, EP3, and EP4) in tumors. This preclinical study provides evidence that the chemotherapeutic effect of GSPs on lung cancer cells in vitro and in vivo is mediated, at least in part, through the inhibition of COX-2 expression and subsequently the inhibition of PGE 2 and PGE 2 receptors.Mol Cancer Ther; 9(3); 569-80. ©2010 AACR.

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Section: Discussionsupporting

confidence: 91%

Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors

Sharma

Meeran

Katiyar

2010

Molecular Cancer Therapeutics

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“…Among these, PI3K-Akt activation by TGF-β induces FOXO3a phosphorylation that results in decreased BCL-2 interacting mediator of cell death (BIM) and Mn-SOD. In contrast, another study has demonstrated that the PI3K-Akt pathway acts as a survival and antiapoptotic signal in the renal cells [46]. Overall, the data from the present study indicate that diabetes increases PI3K-Akt phosphorylation and FOXO3a phosphorylation, and this is accompanied by significant changes in the expression of key FOXO3a target genes, as reflected by the decreases in antiapoptotic BCL-2 and the antioxidants SOD1 and SOD2, and the increase in the expression of the pro-apoptotic gene Bax.…”

Section: Discussionmentioning

confidence: 90%

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

et al. 2012

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Aims/hypothesis Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. Methods Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. Results The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/ lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. Conclusions/interpretation The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

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“…It is generally accepted that Akt is a critical survival signal, which is involved in cancer development and progression and chemoresistance [11]. Although cancer cells acquire resistance to anti-cancer agents through Akt, either constitutive or induced by anti-cancer drugs, the molecular mechanisms underlying anti-cancer drug-induced Akt activation are not well elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The serine-threonine kinase Akt/protein kinase B is a well-known cell survival signal that contributes chemoresistance in a variety of cancer cells [11]. A recent study [12] has demonstrated that Akt overexpression decreases the chemosensitivity of gastric cancer cells to CDDP in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

Park

Yoon

et al. 2013

Gastric Cancer

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Background Cisplatin (CDDP) is one of the most important chemotherapeutic agents in the treatment of advanced gastric cancer, but its efficacy is limited by CDDP resistance. Because the transcription factor FOXO1 is related to chemoresistance in various cancer cells, we investigated the function of FOXO1 in CDDP resistance in human gastric cancer cells. Methods Human gastric cancer cell lines MKN45 and SNU-601 were used. FOXO1 activation was modulated by transfection of FOXO1 AAA mutant gene or FOXO1 shRNA. The effects of FOXO1 on cell growth and CDDP cytotoxicity were assessed by crystal violet assay. Protein expressions of FOXO1, p110a, pAkt, and Akt were analyzed by Western blotting, and FOXO1 mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction. FOXO1 activity was determined by luciferase reporter assay, and cell apoptosis was assessed by DAPI staining and Western blotting for PARP cleavage. Results Cisplatin treatment induced FOXO1 expression and activation in both gastric cancer cell lines. FOXO1 overexpression increased the CDDP resistance without changes in cell growth, whereas FOXO1 silencing enhanced CDDP cytotoxicity along with apoptotic characteristics. Both constitutive and CDDP-induced FOXO1 activations were accompanied by an increase in p110a and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression. Conclusion FOXO1 inhibits CDDP-induced apoptosis in gastric cancer cells via activating PI3K/Akt pathway. Thus, FOXO1 may be an useful pharmacological indicator to predict CDDP efficacy in gastric cancer treatment.

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The PI3-Kinase-Akt Pathway Promotes Mesangial Cell Survival and Inhibits Apoptosis In Vitro via NF-κB and Bad

Cited by 101 publications

References 32 publications

Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors

Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

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