title: Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis.
abstract: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a vital transcription factor that regulates multiple important biological processes, including the epithelial-mesenchymal transition (EMT) and metastasis of breast cancer. Sinomenine is an isoquinoline well known for its remarkable curative effect on rheumatic and arthritic diseases and can induce apoptosis of several cancer cell types. Recently, sinomenine was reported as a tumor suppressor via inhibiting cell proliferation and inducing apoptosis. However, the role and mechanism of sinomenine in invasion and metastasis of breast cancer are largely unknown. Here, we report that sinomenine suppressed the invasion and migration of MDA-MB-231 and 4T1 breast cancer cells in a dose-dependent manner. We detected binding of NF-κB to the inhibitor of NF-κB (IκB) after the MDA-MB-231 cells were treated with 0.25, 0.5, and 1 mM sinomenine. Co-IP analysis revealed that sinomenine enhanced the binding of NF-κB and IκB in a dose-dependent manner, suggesting that sinomenine had an effect on inactivation of NF-κB. Western blotting and ELISA approaches indicated that the suppression effect was closely associated with the phosphorylation of IκB kinase (IKK) and its negative regulator CUEDC2. Sinomenine treatment decreased miR-324-5p expression, thus increased the level of its target gene CUEDC2, and then blocked the phosphorylation of IKK through altering the upstream axis. Finally, transfection of a miR-324-5p mimic inhibited the suppression of invasion and metastasis of MDA-MB-231 and 4T1 cell by sinomenine, providing evidence that sinomenine treatment suppressed breast cancer cell invasion and metastasis via regulation of the IL4/miR-324-5p/CUEDC2 axis. Our findings reveal a novel mechanism by which sinomenine suppresses cancer cell invasion and metastasis, i.e., blocking NF-κB activation.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China. Electronic address: qinlingsongxa@163.com.
authors.forename: Lingqin
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018716:Molecular Mimicry; D009019:Morphinans / Q000008:administration & dosage / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D008517:Phytotherapy
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; C519556:CUEDC2 protein, human; D002352:Carrier Proteins; D020672:I-kappa B Proteins; C508598:IL4 protein, human; C000599310:MIRN324 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009019:Morphinans; D016328:NF-kappa B; D015847:Interleukin-4; C009271:sinomenine
keywords: CUEDC2; IKK phosphorylation; Invasion and metastasis; NF-κB; Sinomenine