MicroRNA-137 inhibits autophagy and chemosensitizes pancreatic cancer cells by targeting ATG5

•Doxorubicin (Dox) induced autophagy but downregulated the expression level of miR-137 in PC cells.•MiR-137 enhanced the ability of Dox to inhibit cell survival and induce cell apoptosis via regulating autophagy in PC cells.•MiR-137 sensitized PANC-1 cells to Dox through inhibiting ATG5 and autophag...

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Published in:The international journal of biochemistry & cell biology 2019-06, Vol.111, p.63-71
Main Authors: Wang, Zhi-Chao, Huang, Fei-Zhou, Xu, Hong-Bo, Sun, Ji-Chun, Wang, Chang-Fa
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Apoptosis - genetics
ATG5
Autophagy
Autophagy - drug effects
Autophagy - genetics
Autophagy-Related Protein 5 - genetics
Cell Line, Tumor
Cell Transformation, Neoplastic
Chemosensitivity
Down-Regulation - drug effects
Down-Regulation - genetics
Doxorubicin - pharmacology
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Female
Humans
Mice
MicroRNAs - genetics
miR-137
Pancreatic Neoplasms - pathology
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Summary:•Doxorubicin (Dox) induced autophagy but downregulated the expression level of miR-137 in PC cells.•MiR-137 enhanced the ability of Dox to inhibit cell survival and induce cell apoptosis via regulating autophagy in PC cells.•MiR-137 sensitized PANC-1 cells to Dox through inhibiting ATG5 and autophagy in vitro and in vivo. Autophagy play an important role in tumor chemotherapy resistance. It has been reported that miR-137 expression was reducedand involved in the regulation of sensitivity of PC cells to chemotherapy. However, little is known about the underlying molecular mechanisms. In this study, we hypothesized that miR-137 might sensitize PC cells to chemotherapy thought regulating cell autophagy. Cell survival was determined with MTT assay. Apoptotic cells were assessed with flow cytometric analysis. Fluorescence intensity of GFP-LC3 and RFP-GFP-LC3 were examined with immunofluorescence analysis to determine the autophagy and autophagic flux level. Western blotting assay was used to determine protein expression levels of LC3II/LC3I, P62, FUNDC1 and ATG5. mRNA expression level of miR-137 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Dual-luciferase reporter assay was used to evaluate the directly binding of miR-137 with its targets. Xenograft model was setup to evaluate tumor growth. The results showed that doxorubicin (Dox) induced autophagy but downregulated the expression level of miR-137 in pancreatic cancer (PC) cells. In turn, overexpression of miR-137 enhanced the effect of Dox on decreasing cell survival, inducing cell apoptosis and inhibiting autophagy rather than influencing autophagic flux in PC cells. Further mechanistic study identified that ATG5 was a direct target of miR-137. Moreover, overexpression of ATG5 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-137. We also demonstrated that miR-137 sensitized PANC-1 cells to Dox through inhibiting ATG5 and autophagy in vivo. Our findings demonstrated for the first time that miR-137 was able to promote sensitivity of PC cells to chemotherapy via inhibition of autophagy mediated by ATG5. Therefore, miR-137 may act as a potential therapeutic target for pancreatic cancer.
ISSN:1357-2725
1878-5875
DOI:10.1016/j.biocel.2019.01.020