title: CBX8 antagonizes the effect of Sirtinol on premature senescence through the AKT-RB-E2F1 pathway in K562 leukemia cells.
abstract: Although tyrosine kinase inhibitor (TKI) therapies are highly effective in the treatment of chronic myeloid leukemia (CML), frequent recurrence limits their usage and demands new approaches for CML therapy. Stress-induced premature senescence (SIPS) is considered a potential anticancer treatment, but the underlying mechanism remains elusive. Here, we report that Sirtinol, a known SIRT1 inhibitor, induces premature senescence and growth arrest in K562 CML cells. Chromobox homolog 8 (CBX8) suppresses the Sirtinol-induced premature senescence, which is reversed by CBX8 knockdown. Upon Sirtinol treatment, the phosphorylation of AKT1, p27KIP1 and RB is severely downregulated. However, CBX8 overexpression enhances phosphorylation and, thereby, promotes the transcriptional activity of E2F1, both of which are impaired upon CBX depletion. These data suggest that CBX8 modulates SIPS through the RB-E2F1 pathway in CML cells and provide important insight into its application in CML treatment.
authors.affiliation: Department of Molecular Biology, Dankook University, Yongin-si, Gyeonggi-do, 448-701, South Korea.
authors.forename: Sang Hyup
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology/Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul, 143-747, South Korea.
authors.forename: Soo-Jong
authors.initials: SJ
authors.lastname: Um
authors.affiliation: Department of Molecular Biology, Dankook University, Yongin-si, Gyeonggi-do, 448-701, South Korea. Electronic address: nbrejk@dankook.ac.kr.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004336:Drug Antagonism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009284:Naphthols / Q000008:administration & dosage*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C570428:CBX8 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009284:Naphthols; D016160:Retinoblastoma Protein; C439060:sirtinol; D063150:Polycomb Repressive Complex 1; D051058:Oncogene Protein v-akt
keywords: CBX8; Leukemia; Premature senescence; RB-E2F1; SIRT1