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Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer.

ABSTRACT: Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression of miR-708-5p, leading to suppression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) expression and subsequently induces apoptosis of prostate cancer cells through the ER stress pathway. Further, miR-708-5p-induced knockdown of NNAT is associated with downregulated intracellular calcium levels and induced malformation of ER-ribosome structure revealed by electronic microscopy. Meanwhile, the unfolded protein response regulator CHOP, p-eIF2?, calreticulin, GRP78 and ATP2A1, all of which are also considered as ER stress markers, are upregulated by metformin and miR-708-5p. Taken together, our findings clearly demonstrate that metformin stimulates increased expression of miR-708-5p to target the NNAT-mediated response to ER stress and apoptosis. This novel regulatory mechanism of metformin in prostate cancer cells not only advances our knowledge on the molecular mechanism of metformin but also provides a promising therapeutic strategy by targeting miR-708-5p and NNAT for prostate cancer treatment.

SUBMITTER: Yang J

PROVIDER: S-EPMC4491613 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer.

Yang J J Wei J J Wu Y Y Wang Z Z Guo Y Y Lee P P Li X X

Oncogenesis 20150615

Although the antitumor role of metformin has been widely reported, the molecular mechanism of this biguanide agent in the inhibition of tumor progression remains unclear. Here, we identified miR-708-5p as a novel target of metformin in prostate cancer cells. Metformin promotes increased expression of miR-708-5p, leading to suppression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) expression and subsequently induces apoptosis of prostate cancer cells through the ER stress pathw ...[more]

PMID: 26075749

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Project description:BACKGROUND:Duchenne (DMD) and Becker (BMD) muscular dystrophies are caused by mutations in the DMD gene coding for dystrophin, a protein being part of a large sarcolemmal protein scaffold that includes the neuronal nitric oxide synthase (nNOS). The nNOS was shown to play critical roles in a variety of muscle functions and alterations of its expression and location in dystrophic muscle fiber leads to an increase of the muscle fatigability. We previously revealed a decrease of nNOS expression in BMD patients all presenting a deletion of exons 45 to 55 in the DMD gene (BMDd45-55), impacting the nNOS binding site of dystrophin. Since several studies showed deregulation of microRNAs (miRNAs) in dystrophinopathies, we focused on miRNAs that could target nNOS in dystrophic context. METHODS:By a screening of 617 miRNAs in BMDd45-55 muscular biopsies using TLDA and an in silico study to determine which one could target nNOS, we selected four miRNAs. In order to select those that targeted a sequence of 3'UTR of NOS1, we performed luciferase gene reporter assay in HEK393T cells. Finally, expression of candidate miRNAs was modulated in control and DMD human myoblasts (DMDd45-52) to study their ability to target nNOS. RESULTS:TLDA assay and the in silico study allowed us to select four miRNAs overexpressed in muscle biopsies of BMDd45-55 compared to controls. Among them, only the overexpression of miR-31, miR-708, and miR-34c led to a decrease of luciferase activity in an NOS1-3'UTR-luciferase assay, confirming their interaction with the NOS1-3'UTR. The effect of these three miRNAs was investigated on control and DMDd45-52 myoblasts. First, we showed a decrease of nNOS expression when miR-708 or miR-34c were overexpressed in control myoblasts. We then confirmed that DMDd45-52 cells displayed an endogenous increased of miR-31, miR-708, and miR-34c and a decreased of nNOS expression, the same characteristics observed in BMDd45-55 biopsies. In DMDd45-52 cells, we demonstrated that the inhibition of miR-708 and miR-34c increased nNOS expression, confirming that both miRNAs can modulate nNOS expression in human myoblasts. CONCLUSION:These results strongly suggest that miR-708 and miR-34c, overexpressed in dystrophic context, are new actors involved in the regulation of nNOS expression in dystrophic muscle.

Dataset Information

Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer.

Publications

Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer.

Similar Datasets

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