Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress.
Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with rapid attenuation of the IRE1α and ATF6 pathways but persistent activation of the PERK branch of the unfolded protein response (UPR) in cells. However, melanoma cells are largely resistant to ER stress-induced apoptosis, suggesting that the kinetics and durations of activation of the UPR pathways are deregulated in melanoma cells undergoing ER stress. We show here that the IRE1α and ATF6 pathways are sustained along with the PERK signaling in melanoma cells subjected to pharmacological ER stress, and that this is, at least in part, due to increased activation of the MEK/ERK pathway. In contrast to an initial increase followed by rapid reduction in activation of IRE1α and ATF6 signaling in control cells that were relatively sensitive to ER stress-induced apoptosis, activation of IRE1α and ATF6 by the pharmacological ER stress inducer tunicamycin (TM) or thapsigargin (TG) persisted in melanoma cells. On the other hand, the increase in PERK signaling lasted similarly in both types of cells. Sustained activation of IRE1α and ATF6 signaling played an important role in protecting melanoma cells from ER stress-induced apoptosis, as interruption of IRE1α or ATF6 rendered melanoma cells sensitive to apoptosis induced by TM or TG. Inhibition of MEK partially blocked IRE1α and ATF6 activation, suggesting that MEK/ERK signaling contributed to sustained activation of IRE1α and ATF6. Taken together, these results identify sustained activation of the IRE1α and ATF6 pathways of the UPR driven by the MEK/ERK pathway as an important protective mechanism against ER stress-induced apoptosis in melanoma cells.
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia.
Kwang Hong
KH
Tay
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia.
Qi
Q
Luan
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia; Oncology and Immunology Unit, Calvary Mater Newcastle Mater Hospital, NSW, Australia.
Amanda
A
Croft
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia.
Chen Chen
CC
Jiang
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia.
Lei
L
Jin
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia. Electronic address: Xu.Zhang@newcastle.edu.au.
Xu Dong
XD
Zhang
School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia. Electronic address: Hsin-Yi.Tseng@newcastle.edu.au.
Hsin-Yi
HY
Tseng
D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000633:toxicity; D014415:Tunicamycin / Q000633:toxicity; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D019284:Thapsigargin; D014415:Tunicamycin; D019892:eIF-2 Kinase; C528229:ERN1 protein, human
ERK; Endoplasmic reticulum stress; Melanoma; UPR