Dataset Information

Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression.

ABSTRACT:

Object

The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro.

Materials and methods

To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin-treated MSCs in ischaemic tissues, a murine hindlimb ischaemic model was established.

Results

Under oxidative stress conditions, treatment with melatonin suppressed the activation of ER stress-associated proteins and autophagy-associated proteins acting through upregulation of cellular prion protein (PrP^C ) expression. Consequently, inhibition of apoptotic cell death occurred. Melatonin also promoted the activation of MnSOD and catalase activities in MSCs. In a murine hindlimb ischaemia model, melatonin-treated MSCs also enhanced the functional limb recovery as well as neovascularization. These beneficial effects of melatonin were all blocked by knock-down of PrP^C expression.

Conclusion

Melatonin protects against ER stress/autophagy-induced apoptotic cell death by augmenting PrP^C expression. Thus, melatonin-treated MSCs could be a potential cell-based therapeutic agent for ER stress-induced ischaemic diseases, and melatonin-induced PrP^C might be a key molecule in ameliorating ER stress and autophagy.

SUBMITTER: Lee JH

PROVIDER: S-EPMC6495509 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression.

Lee Jun Hee JH Yoon Yeo Min YM Han Yong-Seok YS Jung Seo Kyung SK Lee Sang Hun SH

Cell proliferation 20181114 2

<h4>Object</h4>The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro.<h4>Materials and methods</h4>To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin-treated MSCs in ischaemic tissues, a mu ...[more]

PMID: 30430685

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Project description:Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5-/- autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.

Dataset Information

Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression.

Object

Materials and methods

Results

Conclusion

Publications

Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression.

Similar Datasets

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