title: Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines.
abstract: Elevated cyclin D1 (CCND1) expression levels in mantle cell lymphoma (MCL) are associated with aggressive clinical manifestations related to chemoresistance, but little is known about how this important proto-oncogene contributes to the resistance of MCL. Here, we showed that RNA interference-mediated depletion of CCND1 increased caspase-3 activities and induced apoptosis in the human MCL lines UPN-1 and JEKO-1. In vitro and xenotransplant studies revealed that the toxic effect of CCND1 depletion in MCL cells was likely due to increase in histone H2AX phosphorylation, a DNA damage marker. DNA fiber analysis suggested deregulated replication initiation after CCND1 depletion as a potential cause of DNA damage. Finally, in contrast to depletion or inhibition of cyclin-dependent kinase 4, CCND1 depletion increased chemosensitivity of MCL cells to replication inhibitors hydroxyurea and cytarabine. Our findings have an important implication for CCND1 as a potential therapeutic target in MCL patients who are refractory to standard chemotherapy.
authors.affiliation: a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.
authors.forename: Atish
authors.initials: A
authors.lastname: Mohanty
authors.affiliation: a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Sandoval
authors.affiliation: b Irell & Manella Graduate School of Biological Sciences , Duarte , CA , USA.
authors.forename: Thai
authors.initials: T
authors.lastname: Tran
authors.affiliation: c Department of Pathology , City of Hope National Medical Center , Duarte , CA , USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bedell
authors.affiliation: d Animal Resource Center , Beckman Research Institute of City of Hope , Duarte , CA , USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: c Department of Pathology , City of Hope National Medical Center , Duarte , CA , USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.affiliation: c Department of Pathology , City of Hope National Medical Center , Duarte , CA , USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Murata-Collins
authors.affiliation: c Department of Pathology , City of Hope National Medical Center , Duarte , CA , USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D019938:Cyclin D1
keywords: Chemoresistance; DNA damage; cyclin D1; mantle cell lymphoma; replication stress