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Search results for: mTOR Inhibitor, Ku 0063794

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#33831291   2021/04/05 To Up

Potentiation of the Anticancer Effects by Combining Docetaxel with Ku-0063794 Against Triple-Negative Breast Cancer Cells.

mTORC1 and mTORC2 inhibition by Ku-0063794 could confer profound anticancer effects against cancer cells because it eliminates feedback activation of Akt. Herein, we aimed to determine anticancer effects of docetaxel and Ku-0063794, individually or in combination, against breast cancer cells, especially triple negative breast cancer (TNBC) cells.
Ye-Won Jeon, Ok-Hee Kim, Jin Sun Shin, Ha Eun Hong, Cho Hee Kim, Say-June Kim

2487 related Products with: Potentiation of the Anticancer Effects by Combining Docetaxel with Ku-0063794 Against Triple-Negative Breast Cancer Cells.

1 kit(96 Wells)100ul

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#33799789   2021/03/11 To Up

Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p.

It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)-the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225.
Ho Joong Choi, Jung Hyun Park, Ok-Hee Kim, Kee-Hwan Kim, Ha Eun Hong, Haeyeon Seo, Say-June Kim

1153 related Products with: Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p.

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#33549048   2021/02/06 To Up

Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK.

The PI 3-kinase (PI3K) pathway has been implicated as a target for melanoma therapy.
Khanh B Tran, Sharada Kolekar, Anower Jabed, Patrick Jaynes, Jen-Hsing Shih, Qian Wang, Jack U Flanagan, Gordon W Rewcastle, Bruce C Baguley, Peter R Shepherd

2151 related Products with: Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK.

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#32851605   2020/08/26 To Up

Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition.

CD133 expression in pancreatic cancer correlates with poor prognosis and increased metastasis. CD133 pancreatic cancer cells exhibit cancer stem cell (CSC)-like properties. We established a CD133 cell-rich subline from Capan-1 pancreatic cancer cells as a pancreatic CSC model and compared the effects of KU-0063794, a dual mTORC1/mTORC2 inhibitor, against those of mTORC1-specific rapamycin. We found that KU-0063794 prevents sphere formation, a self-renewal index, at high concentrations. Rapamycin inhibited sphere formation but to a lesser degree. In the present study, we aimed to determine the mechanistic roles of mTOR complex 2 (mTORC2) in maintaining CSC-like properties. By examining the PI3K/Akt/mTOR signaling pathway, we observed lower Akt phosphorylation in KU-0063794-treated cells. Phosphorylation of mTORC1 downstream effectors was inhibited by both inhibitors. Thus, mTORC2 activates Akt and modulate stem-like properties, whereas mTORC1 downstream signaling correlates directly with stem-like properties.
Shyuichiro Matsubara, Koichiro Tsukasa, Taisaku Kuwahata, Sonshin Takao

2692 related Products with: Prevention of Akt phosphorylation is a key to targeting cancer stem-like cells by mTOR inhibition.

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#32736679   2020/07/17 To Up

The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development.

Glycine, a non-essential amino acid, exerts concentration-dependent biphasic effects on angiogenesis. Low-doses of glycine promote angiogenesis, whereas high-doses cause anti-angiogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling participates in angiogenesis of both physiological development, and pathological events including tumor and inflammation. We assessed the role of PI3K/Akt/mTOR signaling in vascular development, and the interaction with glycine, using transgenic zebrafish Tg(fli1a:Myr-mCherry) embryos expressing fluorescent proteins in vascular endothelial cells. Treatment with inhibitors of mTORC1 (rapamycin and everolimus), mTORC1/mTORC2 (KU0063794), PI3K (LY29400), and Akt (Akt inhibitor) decreased the development of intersegmental vessels (ISVs). These inhibitors cancelled the angiogenic effects of a low-dose of glycine, while acted synergistically with a high-dose of glycine in anti-angiogenesis. mTOR signaling regulates the gene expression of vascular endothelial growth factor (VEGF), a major angiogenic factor, and nitric oxide (NO) synthase (NOS), an enzyme for the synthesis of an angiogenic mediator NO. Expressions of VEGF and NOS were consistent with the vascular features induced by glycine and an mTOR inhibitor. Our results suggest that PI3K/Akt/mTOR signaling may interact with dose-dependent biphasic effects of exogenous glycine on in vivo angiogenesis. mTOR signaling is a key target for cancer therapy, thus, the combining mTOR inhibitors with glycine may be a potential approach for controlling angiogenesis.
Kiyomi Tsuji-Tamura, Mari Sato, Misato Fujita, Masato Tamura

1345 related Products with: The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development.

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#31982382   2020/01/23 To Up

TXNIP deficiency mitigates podocyte apoptosis via restraining the activation of mTOR or p38 MAPK signaling in diabetic nephropathy.

Thioredoxin-interacting protein (TXNIP), is identified as an inhibitor of the thiol oxidoreductase thioredoxin that acts endogenously, and is increased by high glucose (HG). In this study, we investigated the potential function of TXNIP on apoptosis of podocytes and its potential mechanism in vivo and in vitro in diabetic nephropathy (DN). TXNIP silencing attenuated HG-induced apoptosis and obliterated the activation of signaling pathways of mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) in conditionally immortalized mouse podocytes. Furthermore, the Raptor and Rictor shRNAs, mTOR specific inhibitor KU-0063794 and p38 MAPK inhibitor SB203580 were used to assess the role of mTOR or p38 MAPK pathway on podocyte apoptosis induced by HG. The Rictor and Raptor shRNAs and KU-0063794 appeared to reduce HG-induced apoptosis in podocytes. Simultaneously, SB203580 could also restrain HG-induced apoptosis in podocytes. Streptozotocin rendered equivalent diabetes in TXNIP-/- (TKO) and wild-type (WT) control mice. TXNIP deficiency mitigated renal injury in diabetic mice. Additionally, TXNIP deficiency also descended the apoptosis-related protein and Nox4 levels, the mTOR signaling activation and the p38 MAPK phosphorylation in podocytes of diabetic mice. All these data indicate that TXNIP deficiency may mitigate apoptosis of podocytes by inhibiting p38 MAPK or mTOR signaling pathway in DN, underlining TXNIP as a putative target for therapy.
Shan Song, Duojun Qiu, Yuhan Wang, Jinying Wei, Haijiang Wu, Ming Wu, Shuai Wang, Xinbo Zhou, Yonghong Shi, Huijun Duan

1204 related Products with: TXNIP deficiency mitigates podocyte apoptosis via restraining the activation of mTOR or p38 MAPK signaling in diabetic nephropathy.

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#31726709   2019/11/12 To Up

A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis.

Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G/G cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.
Andreas Kroh, Jeanette Walter, Herdit Schüler, Jochen Nolting, Roman Eickhoff, Daniel Heise, Ulf Peter Neumann, Thorsten Cramer, Tom Florian Ulmer, Athanassios Fragoulis

1315 related Products with: A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis.

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#31499159   2019/09/06 To Up

mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation.

Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4 ± 1.3% to 46.1 ± 2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/β, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.
Koki Abe, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tatsuya Sato, Hidemichi Kouzu, Kei Nakata, Wataru Ohwada, Yukishige Kimura, Hirohito Sugawara, Satoru Shibata, Yusuke Igaki, Shoya Ino, Tetsuji Miura

2701 related Products with: mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation.

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#30746698   2019/02/11 To Up

Thioredoxin-interacting protein deficiency alleviates phenotypic alterations of podocytes via inhibition of mTOR activation in diabetic nephropathy.

Thioredoxin-interacting protein (TXNIP) is induced by high glucose (HG), whereupon it acts to inhibit thioredoxin, thereby promoting oxidative stress. We have found that TXNIP knockdown in human renal tubular cells helped prevent the epithelial-to-mesenchymal transition (EMT). Here, we studied the potential effect of TXNIP on podocyte phenotypic alterations in diabetic nephropathy (DN) in vivo and in vitro. In conditionally immortalized mouse podocytes under HG conditions, knocking down TXNIP disrupted EMT, reactive oxygen species (ROS) production, and mammalian target of rapamycin (mTOR) pathway activation. Further, Raptor short hairpin RNA (shRNA), Rictor shRNA, and mTOR specific inhibitor KU-0063794 were used to assess if the mTOR signal pathway is involved in HG-induced EMT in podocytes. We found that Raptor shRNA, Rictor shRNA, and KU-0063794 could all restrain HG-induced EMT and ROS production in podocytes. In addition, antioxidant Tempol or N-acetylcysteine presented a prohibitive effect on HG-induced EMT in podocytes. Streptozotocin was utilized to render equally diabetic in wild-type (WT) control and TXNIP (TKO) mice. Diabetes did not increase levels of 24-hr urinary protein, serum creatinine, blood urea nitrogen, and triglyceride in TXNIP mice. Podocyte phenotypic alterations and podocyte loss were detected in WT but not in TKO diabetic mice. Oxidative stress was also suppressed in diabetic TKO mice relative to WT controls. Also, TXNIP deficiency suppresses the activation of mTOR in glomeruli of streptozotocin-induced diabetic mice. Moreover, TXNIP expression, mTOR activation, Nox1, and Nox4 could be detected in renal biopsy tissues of patients with DN. This suggests that decreased TXNIP could ameliorate phenotypic alterations of podocytes via inhibition of mTOR in DN, highlighting TXNIP as a promising therapeutic target.
Shan Song, Duojun Qiu, Yonghong Shi, Shuai Wang, Xinbo Zhou, Nan Chen, Jinying Wei, Ming Wu, Haijiang Wu, Huijun Duan

1742 related Products with: Thioredoxin-interacting protein deficiency alleviates phenotypic alterations of podocytes via inhibition of mTOR activation in diabetic nephropathy.

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