The PI3K/Akt and mTOR/P70S6K Signaling Pathways in Human Uveal Melanoma Cells: Interaction with B-Raf/ERK

Babchia, Narjes; Calipel, Armelle; Mouriaux, Frédéric; Faussat, Anne-Marie; Mascarelli, Frédéric

doi:10.1167/iovs.09-3974

Cited by 101 publications

(88 citation statements)

References 44 publications

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“…However, MEK inhibitors cause cell-cycle arrest without significant cell death. The PI3K/AKT and mTOR/p70S6K pathways are critical for tumorigenesis, and the targeting of PI3K while inhibiting ERK has been shown to reduce the proliferation of uveal melanoma cells (8,16,17). Interestingly, we have shown that the constitutively active mutant GNAQ signals not only to ERK but also to AKT, possibly through PI3K direct binding (29) or cross talk between GPCR and receptor tyrosine kinase (RTK)-mediated signaling pathways (30,31).…”

Section: Discussionmentioning

confidence: 90%

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Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death

Ambrosini

Musi

et al. 2013

Molecular Cancer Therapeutics

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Oncogenic mutations in GNAQ and GNA11 genes are found in 80% of uveal melanoma. These mutations result in the activation of the RAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogenactivated protein kinases. In this study, using a siRNA strategy, we show that mutant GNAQ signals to both MEK and AKT, and that combined inhibition of these pathways with the MEK inhibitor selumetinib (AZD6244) and the AKT inhibitor MK2206 induced a synergistic decrease in cell viability. This effect was genotype dependent as autophagic markers like beclin1 and LC3 were induced in GNAQ-mutant cells, whereas apoptosis was the mechanism of cell death of BRAF-mutant cells, and cells without either mutation underwent cell-cycle arrest. The inhibition of MEK/ATK pathways induced activation of AMP-activated protein kinase (AMPK) in the GNAQ-mutant cells. The downregulation of AMPK by siRNA or its inhibition with compound C did not rescue the cells from autophagy, rather they died by apoptosis, defining AMPK as a key regulator of mutant GNAQ signaling and a switch between autophagy and apoptosis. Furthermore, this combination treatment was effective in inhibiting tumor growth in xenograft mouse models. These findings suggest that inhibition of MEK and AKT may represent a promising approach for targeted therapy of patients with uveal melanoma. Mol Cancer Ther; 12(5); 768-76. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 90%

“…It has been reported that GNAQ binds and signals to phosphoinositide-3 kinase (PI3K; refs. [13][14][15], and that targeting PI3K/AKT pathway while inhibiting MEK/ERK is an effective approach to reduce the proliferation of uveal melanoma (8,16,17). However, the mechanisms involved in these processes are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death

Ambrosini

Musi

et al. 2013

Molecular Cancer Therapeutics

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“…Self-sufficiency in growth signals Gain of cell cycle stimulator-activation of pathways The PI3K-AKT prosurvival pathway is constitutively activated in UM. LOH of the PTEN locus occurs in 76% of UM [17][18][19][20][21] The RAF/MEK/ERK pathway is constitutively activated: activating mutations in GNAQ or GNA11 occur in 480% of UM and can activate the RAF/ MEK/ERK pathway 11,[22][23][24][25][26][27][28] …”

Section: The Hallmarks Of Cancermentioning

confidence: 99%

“…15 The p53 pathway is inhibited downstream to p53 in many UM, 30 and this may be a consequence of MDM2 overexpression, which is also common in UM and associated with a poor outcome. 13,15 The PI3K/AKT pathway is constitutively activated in most UM 17 (Table 1). It has been demonstrated using immunohistochemistry that phosphorylated AKT correlates with poor prognosis in UM.…”

Section: Molecular Pathway Defects In Primary Ummentioning

confidence: 99%

Molecular Pathology of Uveal Melanoma

Coupland

Lake

Damato

2014

Clinical Ophthalmic Oncology

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Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligationdependent probe amplification, and singlenucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

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“…The PI3K/Akt pathway stimulates cell growth and is upregulated in cancer cells [10][11][12]. In addition, this pathway deserves further research into its role in supporting cell survival [13,14].…”

Section: Short-communicationmentioning

confidence: 99%

Docosahexaenoic Acid Modulates Oxidative Stress over PI3K Signaling Pathway Activation in Age Related Macular Degeneration

Babchia¹,

A²,

Leclère³

et al. 2017

J Cell Signal

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The PI3K/Akt and mTOR/P70S6K Signaling Pathways in Human Uveal Melanoma Cells: Interaction with B-Raf/ERK

Cited by 101 publications

References 44 publications

Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death

Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death

Molecular Pathology of Uveal Melanoma

Docosahexaenoic Acid Modulates Oxidative Stress over PI3K Signaling Pathway Activation in Age Related Macular Degeneration

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