Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers

被引:317
作者
Roberson, RS
Kussick, SJ
Vallieres, E
Chen, SYJ
Wu, DY
机构
[1] Vet Adm Puget Sound Hlth Care Syst, Dept Med, Div Med Oncol, Seattle Div, Seattle, WA 98108 USA
[2] Univ Washington, Dept Surg, Seattle, WA 98195 USA
[3] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
[4] Univ Washington, Dept Med, Div Med Oncol, Seattle, WA 98195 USA
关键词
D O I
10.1158/0008-5472.CAN-04-1270
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-smatl 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/Cdkl. The escape from ACS can be disrupted by Cdc2/Cdkl kinase inhibitors or by knockdown of Cdc2/Cdkl with small interfering RNA and can be promoted by expression of exogenous Cdc2/Cdkl. We also present evidence that ACS occurs in vivo in human lung cancer following induction chemotherapy. Viable tumors following chemotherapy also overexpress Cdc2/Cdkl. We propose that ACS is a mechanism of in vivo tumor response and that mechanisms aberrantly up-regulate Cdc2/Cdkl promotes escape from the senescence pathway may be involved in a subset of tumors and likely accounts for tumor recurrence/progression.
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收藏
页码:2795 / 2803
页数:9
相关论文
共 51 条
[1]   Survivin, versatile modulation of cell division and apoptosis in cancer [J].
Altieri, DC .
ONCOGENE, 2003, 22 (53) :8581-8589
[2]   Expression of Cdc2 and cyclin B1 in Helicobacter pylori-associated gastric MALT and MALT lymphoma -: Relationship to cell death, proliferation, and transformation [J].
Banerjee, SK ;
Weston, AP ;
Zoubine, MN ;
Campbell, DR ;
Cherian, R .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 156 (01) :217-225
[3]   Reversal of human cellular senescence:: roles of the p53 and p16 pathways [J].
Beauséjour, CM ;
Krtolica, A ;
Galimi, F ;
Narita, M ;
Lowe, SW ;
Yaswen, P ;
Campisi, J .
EMBO JOURNAL, 2003, 22 (16) :4212-4222
[4]   Butyrolactone: More than a Kinase Inhibitor? [J].
Bloom, Joanna ;
Pagano, Michele .
CELL CYCLE, 2002, 1 (02) :117-+
[5]  
BOND JA, 1994, ONCOGENE, V9, P1885
[6]  
Bond JA, 1999, MOL CELL BIOL, V19, P3103
[7]   Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines [J].
Bryan, TM ;
Englezou, A ;
DallaPozza, L ;
Dunham, MA ;
Reddel, RR .
NATURE MEDICINE, 1997, 3 (11) :1271-1274
[8]   Chemotherapy for advanced non-small-cell lung cancer: Who, what, when, why? [J].
Bunn, PA .
JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (18) :23S-33S
[9]   Cellular senescence as a tumor-suppressor mechanism [J].
Campisi, J .
TRENDS IN CELL BIOLOGY, 2001, 11 (11) :S27-S31
[10]   Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent [J].
Chang, BD ;
Swift, ME ;
Shen, M ;
Fang, J ;
Broude, EV ;
Roninson, IB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (01) :389-394