title: Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers.
abstract: Accelerated cellular senescence (ACS) has been described for tumor cells treated with chemotherapy and radiation. Following exposure to genotoxins, tumor cells undergo terminal growth arrest and adopt morphologic and marker features suggestive of cellular senescence. ACS is elicited by a variety of chemotherapeutic agents in the p53-null, p16-deficient human non-small cell H1299 carcinoma cells. After 10 to 21 days, infrequent ACS cells (1 in 10(6)) can bypass replicative arrest and reenter cell cycle. These cells express senescence markers and resemble the parental cells in their transcription profile. We show that these escaped H1299 cells overexpress the cyclin-dependent kinase Cdc2/Cdk1. The escape from ACS can be disrupted by Cdc2/Cdk1 kinase inhibitors or by knockdown of Cdc2/Cdk1 with small interfering RNA and can be promoted by expression of exogenous Cdc2/Cdk1. We also present evidence that ACS occurs in vivo in human lung cancer following induction chemotherapy. Viable tumors following chemotherapy also overexpress Cdc2/Cdk1. We propose that ACS is a mechanism of in vivo tumor response and that mechanisms aberrantly up-regulate Cdc2/Cdk1 promotes escape from the senescence pathway may be involved in a subset of tumors and likely accounts for tumor recurrence/progression.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Veterans Administration Puget Sound Health Care System, Seattle Division, Washington 98108, USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Roberson
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kussick
authors.forename: Eric
authors.initials: E
authors.lastname: Vallieres
authors.forename: Szu-Yu J
authors.initials: SY
authors.lastname: Chen
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Wu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D012109:Research Support as Topic; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D016190:Carboplatin; D016203:CDC2 Protein Kinase; D017239:Paclitaxel; D002166:Camptothecin