A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment

Lili Jiang, Dan Zang, Songgang Yi, Xiaofen Li, Changshan Yang, Xiaoxian Dong, Chong Zhao, Xiaoying Lan, Xin Chen, Shouting Liu, Ningning Liu, Hongbiao Huang, Xianping Shi, Xuejun Wang, Jinbao Liu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number21565
JournalScientific reports
Volume6
DOIs
StatePublished - Feb 22 2016

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Eukaryotic Initiation Factor-2
MicroRNAs
Endoplasmic Reticulum Stress
Cell Survival
Neoplasms
Up-Regulation
Proteasome Inhibitors
Secretory Pathway
Protein Transport
Proteasome Endopeptidase Complex
Endoplasmic Reticulum
Carcinogenesis
Cell Proliferation
Bortezomib
Apoptosis

ASJC Scopus subject areas

  • General

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A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment. / Jiang, Lili; Zang, Dan; Yi, Songgang; Li, Xiaofen; Yang, Changshan; Dong, Xiaoxian; Zhao, Chong; Lan, Xiaoying; Chen, Xin; Liu, Shouting; Liu, Ningning; Huang, Hongbiao; Shi, Xianping; Wang, Xuejun; Liu, Jinbao.

In: Scientific reports, Vol. 6, 21565, 22.02.2016.

Research output: Contribution to journalArticle

Jiang, L, Zang, D, Yi, S, Li, X, Yang, C, Dong, X, Zhao, C, Lan, X, Chen, X, Liu, S, Liu, N, Huang, H, Shi, X, Wang, X & Liu, J 2016, 'A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment', Scientific reports, vol. 6, 21565. https://doi.org/10.1038/srep21565
Jiang, Lili ; Zang, Dan ; Yi, Songgang ; Li, Xiaofen ; Yang, Changshan ; Dong, Xiaoxian ; Zhao, Chong ; Lan, Xiaoying ; Chen, Xin ; Liu, Shouting ; Liu, Ningning ; Huang, Hongbiao ; Shi, Xianping ; Wang, Xuejun ; Liu, Jinbao. / A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment. In: Scientific reports. 2016 ; Vol. 6.
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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.",
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AU - Jiang, Lili

AU - Zang, Dan

AU - Yi, Songgang

AU - Li, Xiaofen

AU - Yang, Changshan

AU - Dong, Xiaoxian

AU - Zhao, Chong

AU - Lan, Xiaoying

AU - Chen, Xin

AU - Liu, Shouting

AU - Liu, Ningning

AU - Huang, Hongbiao

AU - Shi, Xianping

AU - Wang, Xuejun

AU - Liu, Jinbao

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