Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death Journal Article

Authors: Ambrosini, G.; Musi, E.; Ho, A. L.; de Stanchina, E.; Schwartz, G. K.
Article Title: Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent autophagic cell death
Abstract: 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 mitogen-activated 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. ©2013 American Association for Cancer Research.
Journal Title: Molecular Cancer Therapeutics
Volume: 12
Issue: 5
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2013-05-01
Start Page: 768
End Page: 776
Language: English
DOI: 10.1158/1535-7163.mct-12-1020
PROVIDER: scopus
PUBMED: 23443802
Notes: --- - "Export Date: 3 June 2013" - "CODEN: MCTOC" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Gary Schwartz
    384 Schwartz
  2. Alan Loh Ho
    146 Ho
  3. Elgilda Musi
    8 Musi