Dual inhibition of V600EBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism
Authors
Sánchez Hernández, Irene; Baquero Valls, Pablo; Calleros Basilio, Laura; Chiloeches Gálvez, AntonioIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/59600DOI: 10.1016/j.canlet.2011.09.037
ISSN: 0304-3835
Date
2012-01-28Bibliographic citation
Cancer Letters, 2012, v. 314, n. 2, p. 244-255
Keywords
BRAF
MEK/ERK
Melanoma
Apoptosis
PI3K/AKT/mTOR
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/aceptedVersion
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Elsevier
Access rights
info:eu-repo/semantics/openAccess
Abstract
BRAF is a main oncogene in human melanomas. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with RAF inhibitor Sorafenib induces apoptosis in NPA melanoma cells expressing oncogenic (V600E)BRAF. This effect is mediated through a MEK/ERK-independent mechanism, since treatment with the MEK inhibitor U0126 does not exert any effect. Moreover, we demonstrate that inhibition of the PI3K/AKT/mTOR cascade alone does not increase apoptosis in these cells. However, the blockage of this pathway in cells lacking either BRAF expression or activity cooperates to induce higher levels of apoptosis than those achieved by inhibition of BRAF alone. Consistently, we demonstrate that abrogation of BRAF expression increases AKT and mTOR phosphorylation, suggesting the existence of a compensatory pro-survival mechanism after BRAF depletion. Together, our data provide a rationale for dual targeting of BRAF and PI3K/AKT/mTOR signalling to effectively control melanoma disease.
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