title: A NOXA/MCL-1 Imbalance Underlies Chemoresistance of Malignant Rhabdoid Tumor Cells.
abstract: Malignant rhabdoid tumor (MRT) is a rare aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed that SNF5 contributes to transcriptional activation of NOXA, a pro-apoptotic protein that binds and inhibits the anti-apoptotic protein MCL-1. In this study, we found that NOXA expression was downregulated in MRT cell lines as well as in clinical MRT samples and that ectopically expressed NOXA bound MCL-1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. Consistent with this finding, knockdown of MCL-1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells, and the MCL-1 inhibitor TW-37 synergized with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL-1 pathway may be a potential strategy for the treatment of patients with MRT. J. Cell. Physiol. 231: 1932-1940, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ouchi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Kuwahara
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iehara
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Miyachi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Katsumi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Konishi
authors.affiliation: Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yanagisawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin