title: A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment.
abstract: MicroRNAs (miRs) play pivotal roles in carcinogenesis and endoplasmic reticulum (ER) that performs the folding, modification and trafficking of proteins targeted to the secretory pathway. Cancer cells often endure ER stress during tumor progression but use the adaptive ER stress response to gain survival advantage. Here we report: (i) A group of miRs, including miR-30b-5p and miR-30c-5p, are upregulated by proteasome inhibitor PS-341 treatment, in HepG2 and MDA-MB-453 cells. (ii) Two representative PS-341-induced miRs: miR-30b-5p and miR-30c-5p are found to promote cell proliferation and anti-apoptosis in both tumor cells. (iii) eIF2α is confirmed as the congenerous target of miR-30b-5p and miR-30c-5p, essential to the anti-apoptotic function of these miRs. (iv) Upregulation of miR-30b-5p or miR-30c-5p, which occurs latter than the increase of phosphorylated eIF2α (p-eIF2α) in the cell under ER stress, suppresses the p-eIF2α/ATF4/CHOP pro-apoptotic pathway. (v) Inhibition of the miR-30b-5p or miR-30c-5p sensitizes the cancer cells to the cytotoxicity of proteasome inhibition. In conclusion, we unravels a new miRs-based mechanism that helps maintain intracellular proteostasis and promote cell survival during ER stress through upregulation of miR-30b-5p and miR-30c-5p which target eIF2α and thereby inhibit the p-eIF2α/ATF4/CHOP pro-apoptotic pathway, identifying miR-30b-5p and miR-30c-5p as potentially new targets for anti-cancer therapies.
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Songgang
authors.initials: S
authors.lastname: Yi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.|Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, People's Republic of China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Xianping
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.|Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis* / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D051742:Transcription Factor CHOP / Q000096:biosynthesis
chemical_list: C497109:ATF4 protein, human; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D061988:Proteasome Inhibitors; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000069286:Bortezomib