title: Small interfering RNA targeting Rac1 sensitizes colon cancer to dihydroartemisinin-induced cell cycle arrest and inhibited cell migration by suppressing NFκB activity.
abstract: Dihydroartemisinin (DHA) has recently shown antitumor activity in various cancer cells. The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. In addition, Rac1 plays a major role in activating NFκB-mediated transcription. Both Rac1 and NFκB regulate many properties of the malignant phenotype, including anchorage-independent proliferation and survival, metastasis, and angiogenesis. In this study, for the first time, we demonstrated that Rac1 knockdown can enhance DHA-induced growth inhibition, cell cycle arrest, apoptosis, and migration in both HCT116 and RKO cell lines in vitro. The mechanism is due partially to DHA, and Rac1 siRNA deactivates NFκB activity, so as to decrease tremendously the expression of its target gene products, such as PCNA, cyclin D1, and CDK4; and increase the expression of p21, cleaved-caspase-3, and cleaved-PARP. In our in vivo studies, DHA also manifested remarkably enhanced antitumor effect when combined with Rac1 siRNA. We concluded that inhibition of NFκB activation is one of the mechanisms that Rac1 siRNA dramatically promotes DHAs antitumor effect on human colon cancer.
authors.affiliation: Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Han
authors.forename: Ying
authors.initials: Y
authors.lastname: Luan
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yu
authors.forename: Jingwen
authors.initials: J
authors.lastname: Li
authors.forename: Zicheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Binbin
authors.initials: B
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D037621:Artemisinins / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D016328:NF-kappa B; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; C039060:artenimol; D020830:rac1 GTP-Binding Protein
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