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Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers

¹ Division of Medical Oncology, Department of Medicine, Veterans Administration Puget Sound Health Care System, Seattle Division; ² Division of Medical Oncology, Department of Medicine; ³ Department of Pathology; and ⁴ Department of Surgery, University of Washington, Seattle, Washington

Requests for reprints: Daniel Y. Wu, Division of Medical Oncology, Department of Medicine, Veterans Administration Puget Sound Health Care System, Seattle Division, 111-ONC, 1660 South Columbian Way, Seattle, WA 98108. Phone: 206-764-2709; Fax: 206-764-2598; E-mail: danielw{at}u.washington.edu.

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 10⁶) 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.

Key Words: Cellular Senescence • Chemotherapy • p53-independent • Cdc2/Cdk1

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