A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment.
A microRNA-mediated decrease in eukaryotic initiation factor 2α promotes cell survival during PS-341 treatment.
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DOI：
10.1038/srep21565
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发表时间：
2016-02-22
影响因子：
4.6
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
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
MicroRNAs(MiRs)在肿瘤发生和内质网(ER)中发挥关键作用，内质网执行针对分泌途径的蛋白质的折叠、修饰和运输。癌细胞在肿瘤进展过程中经常承受内质网应激，但利用适应性内质网应激反应获得生存优势。我们报道：(1)蛋白酶体抑制剂PS-341可上调HepG2和MDA-MB-453细胞中的miR，包括miR-30b-5p和miR-30c-5p。(Ii)PS-341诱导的两种具有代表性的miRs：miR-30b-5p和miR-30c-5p在两种肿瘤细胞中都具有促进细胞增殖和抗凋亡的作用。(3)eIF2α被确认为miR-30b-5p和miR-30c-5p的共同靶点，对这些miR的抗凋亡功能至关重要。(4)在内质网应激下，miR-30b-5p或miR-30c-5p的上调晚于细胞内磷酸化eIF_2α(p-eIF_2α)的上调，抑制了p-eIF_2α/ATF_4/CHOP促凋亡通路。(V)抑制miR-30b-5p或miR-30c-5p使癌细胞对蛋白酶体抑制的细胞毒性敏感。总之，我们揭示了一种新的基于miRs的机制，通过上调靶向eIF2α的miR-30b-5p和miR-30c-5p，帮助维持细胞内的蛋白稳定，促进细胞存活，从而抑制p-eIF2α/ATF4/CHOP促凋亡途径，确定miR-30b-5p和miR-30c-5p是潜在的抗癌治疗新靶点。
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.