- Title
- Oncogenic activation of MEK/ERK primes melanoma cells for adaptation to endoplasmic reticulum stress
- Creator
- Croft, Amanda; Tay, Kwang H.; Zhang, Xu D.; Boyd, Suzanah C.; Guo, Su T.; Jiang, Chen C.; Lai, Fritz; Tseng, Hsin-Yi; Jin, Lei; Rizos, Helen; Hersey, Peter
- Relation
- Journal of Investigative Dermatology Vol. 134, p. 488-497
- Publisher Link
- http://dx.doi.org/10.1038/jid.2013.325
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2014
- Description
- 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 BRAFV600E 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 BRAFV600E 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.
- Subject
- melanoma cells; endoplasmic reticulum stress; oncogenic activation; protein
- Identifier
- http://hdl.handle.net/1959.13/1048057
- Identifier
- uon:14866
- Identifier
- ISSN:0022-202X
- Rights
- © 2014. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
- Language
- eng
- Full Text
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