Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis.
The proto-oncogene c-Myc plays critical roles in human malignancies including chronic myeloid leukemia (CML), suggesting that the discovery of specific agents targeting c-Myc would be extremely valuable for CML treatment. Nitidine Chloride (NC), a natural bioactive alkaloid, is suggested to possess...
| Main Authors: | , , , , , , |
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| Format: | Article |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4315404?pdf=render |
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| author | Na Liu Peng Li Shaolei Zang Qiang Liu Daoxin Ma Xiulian Sun Chunyan Ji |
| author_facet | Na Liu Peng Li Shaolei Zang Qiang Liu Daoxin Ma Xiulian Sun Chunyan Ji |
| author_sort | Na Liu |
| collection | DOAJ |
| description | The proto-oncogene c-Myc plays critical roles in human malignancies including chronic myeloid leukemia (CML), suggesting that the discovery of specific agents targeting c-Myc would be extremely valuable for CML treatment. Nitidine Chloride (NC), a natural bioactive alkaloid, is suggested to possess anti-tumor effects. However, the function of NC in leukemia and the underlying molecular mechanisms have not been established. In this study, we found that NC induced erythroid differentiation, accompanied by increased expression of erythroid differentiation markers, e. g. α-, ε-, γ-globin, CD235a, CD71 and α-hemoglobin stabilizing protein (AHSP) in CML cells. We also observed that NC induced apoptosis and upregulated cleaved caspase-3 and Parp-1 in K562 cells. These effects were associated with concomitant attenuation of c-Myc. Our study showed that NC treatment in CML cells enhanced phosphorylation of Thr58 residue and subsequently accelerated degradation of c-Myc. A specific group of miRNAs, which had been reported to be activated by c-Myc, mediated biological functions of c-Myc. We found that most of these miRNAs, especially miR-17 and miR-20a showed strong decrement after NC treatment or c-Myc interference. Furthermore, overexpression of c-Myc or miR-17/20a alleviated NC induced differentiation and apoptosis in K562 cells. More importantly, NC enhanced the effects of imatinib in K562 and primary CML cells. We further found that even imatinib resistant CML cell line (K562/G01) and CML primary cells exhibited high sensitivity to NC, which showed potential possibility to overcome imatinib resistance. Taken together, our results clearly suggested that NC promoted erythroid differentiation and apoptosis through c-Myc-miRNAs regulatory axis, providing potential possibility to overcome imatinib resistance. |
| first_indexed | 2024-12-14T14:58:37Z |
| format | Article |
| id | doaj.art-9a345750a29048649207a903f1c105b4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T14:58:37Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-9a345750a29048649207a903f1c105b42022-12-21T22:56:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01102e011688010.1371/journal.pone.0116880Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis.Na LiuPeng LiShaolei ZangQiang LiuDaoxin MaXiulian SunChunyan JiThe proto-oncogene c-Myc plays critical roles in human malignancies including chronic myeloid leukemia (CML), suggesting that the discovery of specific agents targeting c-Myc would be extremely valuable for CML treatment. Nitidine Chloride (NC), a natural bioactive alkaloid, is suggested to possess anti-tumor effects. However, the function of NC in leukemia and the underlying molecular mechanisms have not been established. In this study, we found that NC induced erythroid differentiation, accompanied by increased expression of erythroid differentiation markers, e. g. α-, ε-, γ-globin, CD235a, CD71 and α-hemoglobin stabilizing protein (AHSP) in CML cells. We also observed that NC induced apoptosis and upregulated cleaved caspase-3 and Parp-1 in K562 cells. These effects were associated with concomitant attenuation of c-Myc. Our study showed that NC treatment in CML cells enhanced phosphorylation of Thr58 residue and subsequently accelerated degradation of c-Myc. A specific group of miRNAs, which had been reported to be activated by c-Myc, mediated biological functions of c-Myc. We found that most of these miRNAs, especially miR-17 and miR-20a showed strong decrement after NC treatment or c-Myc interference. Furthermore, overexpression of c-Myc or miR-17/20a alleviated NC induced differentiation and apoptosis in K562 cells. More importantly, NC enhanced the effects of imatinib in K562 and primary CML cells. We further found that even imatinib resistant CML cell line (K562/G01) and CML primary cells exhibited high sensitivity to NC, which showed potential possibility to overcome imatinib resistance. Taken together, our results clearly suggested that NC promoted erythroid differentiation and apoptosis through c-Myc-miRNAs regulatory axis, providing potential possibility to overcome imatinib resistance.http://europepmc.org/articles/PMC4315404?pdf=render |
| spellingShingle | Na Liu Peng Li Shaolei Zang Qiang Liu Daoxin Ma Xiulian Sun Chunyan Ji Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. PLoS ONE |
| title | Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. |
| title_full | Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. |
| title_fullStr | Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. |
| title_full_unstemmed | Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. |
| title_short | Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. |
| title_sort | novel agent nitidine chloride induces erythroid differentiation and apoptosis in cml cells through c myc mirnas axis |
| url | http://europepmc.org/articles/PMC4315404?pdf=render |
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