title: Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis.
abstract: 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.
authors: Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.
authors: Na
authors: N
authors: Liu
authors: Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.
authors: Peng
authors: P
authors: Li
authors: Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.
authors: Shaolei
authors: S
authors: Zang
authors: Key Lab of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China.
authors: Qiang
authors: Q
authors: Liu
authors: Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.
authors: Daoxin
authors: D
authors: Ma
authors: Key Lab of Otolaryngology, Qilu Hospital of Shandong University, Jinan, China.
authors: Xiulian
authors: X
authors: Sun
authors: Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.
authors: Chunyan
authors: C
authors: Ji
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D041905:Erythroid Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D013912:Threonine; D000068877:Imatinib Mesylate; C013615:nitidine
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