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.
Highlights
Synthesis and maturation of all secretory proteins occur in the endoplasmic reticulum (ER)[13]
Our further investigation demonstrates that miR-30b-5p and miR-30c-5p, which are upregulated after eIF2α phosphorylation has increased, target eIF2α, lead to suppression of the phosphorylated eIF2α (p-eIF2α) -ATF4-CHOP pro-apoptotic pathway, and thereby promote cell proliferation and confer resistance to apoptosis in the cancer cells both under basal culture condition and during proteasome inhibition, unraveling a new miRs-based mechanism for suppressing general protein synthesis and improving cell survival in the unfolded protein response (UPR)
A microarray analysis for miR gene expression was performed in hepatocellular carcinoma HepG2 cells after treatment with a proteasome inhibitor PS-341 (50 nM) for 24 h
Summary
Synthesis and maturation of all secretory proteins occur in the endoplasmic reticulum (ER)[13]. The first-line of reactions to deal with ER stress is to suppress general protein synthesis via PERK-mediated eIF2α phosphorylation and IRE1-mediated cleavage of mRNAs while all the three arms of UPR signaling activate transcription cascades to synthesize selective sets of proteins that can promote protein folding and augment the degradation of unfolded/misfolded ER proteins[23,24] If this response fails, mitogen-activated protein kinases (MAPKs), Jun N-terminal kinase (JNK), and nuclear factor-κ B (NF-κ B) might be activated to induce gene expression performing host protection[25,26,27,28]. Inhibition of either miRs remarkably enhanced the cytotoxicity of proteasome inhibition, which identifies these PS341-induced miRs as potential new targets for anti-cancer therapies
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