The Phosphoinositide 3-Kinase/Akt Pathway: A New Target in Human Renal Cell Carcinoma Therapy

Sourbier, Carole; Lindner, Véronique; Lang, Hervé; Agouni, Abdelali; Schordan, Eric; Danilin, Sabrina; Rothhut, Sylvie; Jacqmin, Didier; Helwig, Jean-Jacques; Massfelder, Thierry

doi:10.1158/0008-5472.can-05-1469

Cited by 140 publications

(140 citation statements)

References 62 publications

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“…Activation of PI3K/Akt regulates the function of a broad array of intracellular proteins involved in fundamental processes, including cell proliferation, cell death, cell motility/adhesion, cell transformation, and neovascularization (36,37). PI3K inhibition enhances chemotherapy-induced tumor cell apoptosis in cancer cells (20). Low levels of activated Akt are observed in human RCC cells (20).…”

Section: Discussionmentioning

confidence: 99%

“…PI3K inhibition enhances chemotherapy-induced tumor cell apoptosis in cancer cells (20). Low levels of activated Akt are observed in human RCC cells (20). Some important factors, including EGF, VEGF, and TGF-b, are involved in the tumorigenesis of human carcinoma through activation of PI3K/Akt signaling cascade (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-a-mediated changes of E-cadherin and vimentin were via the PI3K/Akt and GSK-3b pathways in RCC cells Previous study showed that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway was activated to inhibit GSK-3 kinase in RCC cells (20). GSK-3 kinase has been reported to be involved in the regulation of EMT (11).…”

Section: Tnf-a Enhanced Migration/invasion and Tumorigenicity Of Rcc mentioning

confidence: 99%

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TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

105

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TNF-a is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-a production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-a are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-a induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-a treatment inhibited glycogen synthase kinase 3b (GSK-3b) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3b and suppressed the TNFa-induced EMT of RCC cells. Inactivation of GSK-3b by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3b by transduction of constitutively active GSK-3b into RCC cells suppressed TNFa-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3b, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3b activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3b plays a pivotal role in the TNF-a-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. Ó2012 AACR. IntroductionRenal cell carcinoma (RCC) is the tenth most common cause of cancer-related deaths worldwide (1). Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2, 3). Previous studies indicated immunotherapy is relatively effective against RCC (2, 3). However, the response rate is only 15% to 20% (1-3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Tnf-a Enhanced Migration/invasion and Tumorigenicity Of Rcc mentioning

confidence: 99%

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TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

105

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“…The possible mechanisms by which this pathway regulates NPC proliferation include mutations in PI3K, PTEN deleted from chromosome 10 (PTEN), and Ras oncogene, as well as EGFR amplification (6)(7)(8). Previous studies showed that PI3K/Akt/mTOR signaling is frequently activated in many cancers, including lung, gastric, renal, and ovarian cancers (9)(10)(11)(12), and inhibition of this pathway could increase radiosensitivity (8,(13)(14)(15)(16)(17)(18). NPC cell lines and tissues also overexpressed phosphorylated Akt (p-Akt; refs.…”

Section: Introductionmentioning

confidence: 99%

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Liu

Sun

et al. 2015

Molecular Cancer Therapeutics

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Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual g-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR).Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration-and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G 2 -M cellcycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429-39. Ó2014 AACR.

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“…Akt activation may be an early event in lung tumorigenesis (West et al, 2003). Recent studies reported that the inhibition of PI3K activity by LY294002 reduced human cancer cell growth in vivo and in vitro by apoptosis or G1 cell cycle arrest (Casagrande et al, 1998;Hu et al, 2000;Semba et al, 2002;Gao et al, 2004;Takeda et al, 2004;Sourbier et al, 2006).…”

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confidence: 99%

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

et al. 2008

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c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals, and it is frequently overexpressed in non-small cell lung cancers (NSCLCs). Earlier, we showed that blocking AP-1 by the overexpression of a c-Jun dominant-negative mutant, TAM67, inhibited NSCLC cell growth. The phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway is important in transformation, proliferation, survival and metastasis of NSCLC cells. In this study, we used NCI-H1299 Tet-on clone cells that express TAM67 under the control of inducible promoter to determine the effects of inhibition of AP-1 and PI3K on cell growth. The PI3K inhibitor, LY294002, produced a dose-dependent inhibition of growth in H1299 cells and that inhibition was enhanced by TAM67. TAM67 increased dephosphorylation of Akt induced by LY294002 and reduced the TPA response element DNA-binding of phosphorylated c-Jun. TAM67 increased G1 cell cycle blockade induced by LY294002, which was partially associated with cyclin A decrease and p27 Kip1 accumulation. Furthermore, TAM67 and LY294002 act, at least additively, to inhibit anchorage-independent growth of the H1299 cells. These results suggest that AP-1 and PI3K/Akt pathways play an essential role in the growth of some NSCLC cells.

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The Phosphoinositide 3-Kinase/Akt Pathway: A New Target in Human Renal Cell Carcinoma Therapy

Cited by 140 publications

References 62 publications

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

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