Up-regulation of gamma-synuclein contributes to cancer cell survival under endoplasmic reticulum stress.
Previous studies have demonstrated that gamma-synuclein is overexpressed in a variety of human malignancies. Overexpression of gamma-synuclein in human breast cancer cells leads to an increase in cell motility, resistance to chemotherapeutic drugs, and mitotic checkpoint dysfunction. We report in this study that gamma-synuclein is up-regulated by endoplasmic reticulum stress. The up-regulation of gamma-synuclein expression by endoplasmic reticulum stress is mediated, at least in part, by activation transcription factor (ATF) 4. Knockdown of gamma-synuclein sensitized human breast cancer cells to endoplasmic reticulum stress-induced apoptosis. Induction of apoptosis by endoplasmic reticulum stress when gamma-synuclein was inhibited was dependent on JNK or caspase activation, with caspase-3 and caspase-7 being involved. Treatment with the JNK or caspase-3 and caspase-7 inhibitor partially blocked endoplasmic reticulum stress-induced apoptosis in breast cancer cells transfected with or without the siRNA against gamma-synuclein. Taken together, these data suggest that gamma-synuclein may promote cancer progression by suppressing endoplasmic reticulum stress-induced apoptosis.
Hua
Hui
H
Division of Signal Transduction and Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Xu
Li
L
Wang
Jiao
J
Jing
Jing
J
Luo
Ting
T
Jiang
Yangfu
Y
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation; D051845:gamma-Synuclein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
C497109:ATF4 protein, human; D014408:Biomarkers, Tumor; D061945:Caspase Inhibitors; D034741:RNA, Small Interfering; D051845:gamma-Synuclein; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053179:Caspase 7