title: The involvement of FoxO in cell survival and chemosensitivity mediated             by Mirk/Dyrk1B in ovarian cancer.
abstract: Minibrain-related kinase (Mirk) is a serine/threonine kinase which is also known as the dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B). It is known that Dyrk1A, the closest family member to Mirk/Dyrk1B can mediate cellular localization of mammalian forkhead subclass O (FoxO1), a transcription factor, although the effect of Mirk/Dyrk1B on FoxO factors remains to be defined. In this study, we showed that Mirk/Dyrk1B protein was overexpressed in 5 of 8 ovarian cancer cell lines and negatively correlated with the protein level of FoxO factors (FoxO1+FoxO3A). Knockdown of Mirk by small interfering RNA (siRNA) resulted in cell apoptosis and sensitized cells to cisplatin accompanied by nuclear translocation of FoxO1 and/or FoxO3A as well as increased Bim, TRADD, cleaved caspase-3 and PARP. Furthermore, combined siRNAs of Mirk with FoxO1 and/or FoxO3A led to fewer apoptotic cells and cisplatin sensitivity compared to Mirk siRNA alone, suggesting that FoxO is involved in Mirk-mediated cell survival and chemosensitivity of ovarian cancer. Taken together, Mirk/Dyrk1B plays an important role in ovarian cancer cell survival through modulating FoxO translocation and may be a novel therapeutic target for ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, First Affiliated Hospital, Dalian Medical University, Zhongshan Road 222, Dalian, Liaoning 116011, PR China. jingchun_gao@yahoo.com
authors.forename: Jingchun
authors.initials: J
authors.lastname: Gao
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Hu
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Liao
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Miao
authors.forename: Chao
authors.initials: C
authors.lastname: Pan
authors.forename: Na
authors.initials: N
authors.lastname: Li
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D018613:Microscopy, Confocal; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D000097603:Dyrk Kinases
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000097603:Dyrk Kinases; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human