Format

Send to

Choose Destination
J Invest Dermatol. 2014 Feb;134(2):488-497. doi: 10.1038/jid.2013.325. Epub 2013 Aug 6.

Oncogenic activation of MEK/ERK primes melanoma cells for adaptation to endoplasmic reticulum stress.

Author information

1
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia; Oncology and Immunology Unit, Calvary Mater Newcastle Mater Hospital, Waratah, New South Wales, Australia.
2
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
3
Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
4
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, People's Republic of China.
5
Kolling Institute for Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
6
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia. Electronic address: Xu.Zhang@newcastle.edu.au.

Abstract

Cancer cells commonly undergo chronic endoplasmic reticulum (ER) stress, to which the cells have to adapt for survival and proliferation. We report here that in melanoma cells intrinsic activation of the ER stress response/unfolded protein response (UPR) is, at least in part, caused by increased outputs of protein synthesis driven by oncogenic activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and promotes proliferation and protects against apoptosis induced by acute ER stress. Inhibition of oncogenic BRAF(V600E) or MEK-attenuated activation of inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) signaling of the UPR in melanoma cells. This was associated with decreased phosphorylation of eukaryotic initiation factor 4E (eIF4E) and nascent protein synthesis and was recapitulated by knockdown of eIF4E. In line with this, introduction of BRAF(V600E) into melanocytes led to increases in eIF4E phosphorylation and protein production and triggered activation of the UPR. Similar to knockdown of glucose-regulated protein 78 (GRP78), inhibition of XBP1 decelerated melanoma cell proliferation and enhanced apoptosis induced by the pharmacological ER stress inducers tunicamycin and thapasigargin. Collectively, these results reveal that potentiation of adaptation to chronic ER stress is another mechanism by which oncogenic activation of the MEK/ERK pathway promotes the pathogenesis of melanoma.

PMID:
23921951
DOI:
10.1038/jid.2013.325
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center