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MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.

Wang JX, Zhang XJ, Feng C, Sun T, Wang K, Wang Y, Zhou LY, Li PF - Cell Death Dis (2015)

Bottom Line: DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1).In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis.MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.

ABSTRACT
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.

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MiR-532-3p is not involved in DOX-induced apoptosis in cancer cells. (a) The miR-532-3p levels in cardiomyocytes, Hela, SGC-7901, SW-480 and HEPG-2 cells. *P<0.05 versus cardiomyocytes. (b and c) The miR-532-3p levels in Hela (b) and SGC-7901 (c) cells treated with 2 μM DOX for the indicated times. (d and e) Cell death in Hela (d) and SGC-7901 (e) cells transfected with miR-532-3p antagomir and treated with 2 μM DOX. Data are expressed as the mean±S.D., n=3
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fig7: MiR-532-3p is not involved in DOX-induced apoptosis in cancer cells. (a) The miR-532-3p levels in cardiomyocytes, Hela, SGC-7901, SW-480 and HEPG-2 cells. *P<0.05 versus cardiomyocytes. (b and c) The miR-532-3p levels in Hela (b) and SGC-7901 (c) cells treated with 2 μM DOX for the indicated times. (d and e) Cell death in Hela (d) and SGC-7901 (e) cells transfected with miR-532-3p antagomir and treated with 2 μM DOX. Data are expressed as the mean±S.D., n=3

Mentions: It has been previously found that ARC is also highly expressed in some malignant tumors and some type of cancer cells.22, 23 Our recent studies have shown that DOX led to a decrease in ARC expression levels in Hela and SGC-7901 cells.13 ARC contributes to cell resistance to chemotheraphy by targeting the apoptotic machinery. However, the role of miR-532-3p in DOX-induced apoptosis in cancer cells remains largely unknown. We tested whether miR-532-3p is related to apoptosis in some cancer cells exposed to DOX. MiR-532-3p was expressed at low level in cancer cells, including Hela, SGC-7901, SW-480 and HepG-2, compared with cardiomyocytes (Figure 7a). Expression levels of miR-532-3p were not changed in Hela (Figure 7b), SGC-7901 (Figure 7c), SW-480 (Supplementary Figure S5a) and HepG-2 (Supplementary Figure S5b) cells administered with DOX. Knockdown miR-532-3p had no significant effect on cell death induced by DOX in these cancer cells (Figures 7d and e and Supplementary Figures S5c and d). Taken together, it seems that miR-532-3p is not involved in DOX-induced apoptotic program in cancer cells.


MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.

Wang JX, Zhang XJ, Feng C, Sun T, Wang K, Wang Y, Zhou LY, Li PF - Cell Death Dis (2015)

MiR-532-3p is not involved in DOX-induced apoptosis in cancer cells. (a) The miR-532-3p levels in cardiomyocytes, Hela, SGC-7901, SW-480 and HEPG-2 cells. *P<0.05 versus cardiomyocytes. (b and c) The miR-532-3p levels in Hela (b) and SGC-7901 (c) cells treated with 2 μM DOX for the indicated times. (d and e) Cell death in Hela (d) and SGC-7901 (e) cells transfected with miR-532-3p antagomir and treated with 2 μM DOX. Data are expressed as the mean±S.D., n=3
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig7: MiR-532-3p is not involved in DOX-induced apoptosis in cancer cells. (a) The miR-532-3p levels in cardiomyocytes, Hela, SGC-7901, SW-480 and HEPG-2 cells. *P<0.05 versus cardiomyocytes. (b and c) The miR-532-3p levels in Hela (b) and SGC-7901 (c) cells treated with 2 μM DOX for the indicated times. (d and e) Cell death in Hela (d) and SGC-7901 (e) cells transfected with miR-532-3p antagomir and treated with 2 μM DOX. Data are expressed as the mean±S.D., n=3
Mentions: It has been previously found that ARC is also highly expressed in some malignant tumors and some type of cancer cells.22, 23 Our recent studies have shown that DOX led to a decrease in ARC expression levels in Hela and SGC-7901 cells.13 ARC contributes to cell resistance to chemotheraphy by targeting the apoptotic machinery. However, the role of miR-532-3p in DOX-induced apoptosis in cancer cells remains largely unknown. We tested whether miR-532-3p is related to apoptosis in some cancer cells exposed to DOX. MiR-532-3p was expressed at low level in cancer cells, including Hela, SGC-7901, SW-480 and HepG-2, compared with cardiomyocytes (Figure 7a). Expression levels of miR-532-3p were not changed in Hela (Figure 7b), SGC-7901 (Figure 7c), SW-480 (Supplementary Figure S5a) and HepG-2 (Supplementary Figure S5b) cells administered with DOX. Knockdown miR-532-3p had no significant effect on cell death induced by DOX in these cancer cells (Figures 7d and e and Supplementary Figures S5c and d). Taken together, it seems that miR-532-3p is not involved in DOX-induced apoptotic program in cancer cells.

Bottom Line: DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1).In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis.MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.

ABSTRACT
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.

Show MeSH
Related in: MedlinePlus