Oncogenic activation of MEK/ERK primes melanoma cells for adaptation to endoplasmic reticulum stress.
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.
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.
Amanda
A
Croft
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
Kwang H
KH
Tay
Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Suzanah C
SC
Boyd
Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, People's Republic of China.
Su T
ST
Guo
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
Chen C
CC
Jiang
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
Fritz
F
Lai
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
Hsin-Yi
HY
Tseng
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
Lei
L
Jin
Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Helen
H
Rizos
Kolling Institute for Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
Peter
P
Hersey
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia. Electronic address: Xu.Zhang@newcastle.edu.au.
Xu D
XD
Zhang
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000222:Adaptation, Physiological / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007211:Indoles; D008565:Membrane Proteins; C528407:PLX 4720; D000071701:Regulatory Factor X Transcription Factors; D013449:Sulfonamides; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C403982:ERN2 protein, human; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D004722:Endoribonucleases