title: Momilactone B induces apoptosis and G1 arrest of the cell cycle in human monocytic leukemia U937 cells through downregulation of pRB phosphorylation and induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1.
abstract: Momilactone B, a terpenoid phytoalexin present in rice bran, has been shown to exhibit several biological activities. The present study was conducted using cultured human leukemia U937 cells to elucidate the possible mechanisms by which momilactone B exerts its anticancer activity, which to date has remained poorly understood. Momilactone B treatment of U937 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death as detected by chromatin condensation, DNA fragmentation, the cleavage of poly(ADP-ribose) polymerase and Annexin V-FITC staining. Flow cytometric analysis revealed that momilactone B resulted in G1 arrest in cell cycle progression, which was associated with the dephosphorylation of retinoblastoma protein (pRB) and enhanced binding of pRB with the E2F transcription factor family proteins. Treatment with momilactone B also increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21Waf1/Cip1 in a p53-independent manner, without any noticeable changes in G1 cyclins and cyclin-dependent kinases (Cdks), except a slight decrease in cyclin E. Moreover, in vitro kinase assay indicated that momilactone B significantly decreased Cdk4- and Cdk6-associated kinase activities through a notably increased binding of p21 to Cdk4 and Cdk6. Our results demonstrated that momilactone B caused G1 cell cycle arrest and apoptosis in U937 cells through the induction of p21 expression, inhibition of Cdk/cyclin-associated kinase activities, and reduced phosphorylation of pRB, which may be related to anticancer activity.
authors: Department of Molecular Biology, College of Natural Sciences, Dongeui University, Busan 614-714, Republic of Korea.
authors: Cheol
authors: C
authors: Park
authors: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, Republic of Korea.
authors: Na Young
authors: NY
authors: Jeong
authors: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea.
authors: Gi-Young
authors: GY
authors: Kim
authors: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
authors: Min Ho
authors: MH
authors: Han
authors: Department of Applied Life Science, College of Life and Environmental Science, Konkuk University, Seoul 143-701, Republic of Korea.
authors: Ill-Min
authors: IM
authors: Chung
authors: Department of Urology, Chungbuk National University College of Medicine, Cheongju 361-763, Republic of Korea.
authors: Wun-Jae
authors: WJ
authors: Kim
authors: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714, Republic of Korea.
authors: Young Hyun
authors: YH
authors: Yoo
authors: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
authors: Yung Hyun
authors: YH
authors: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007783:Lactones / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D007783:Lactones; D016160:Retinoblastoma Protein; C477203:momilactone B