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Ataxia Telangiectasia Mutated and p21^CIP1 Modulate Cell Survival of Drug-Induced Senescent Tumor Cells: Implications for Chemotherapy

Authors' Affiliations: ¹ Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano" and Istituto di Endocrinologia e Oncologia Sperimentale-Consiglio Nazionale delle Ricerche Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II," Naples, Italy and ² Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, United Kingdom

Requests for reprints: Hugh J.M. Brady, Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. Phone: 44-20-79052731; Fax: 44-20-78138100; E-mail: h.brady{at}ich.ucl.ac.uk.

Purpose: Premature or stress-induced senescence is a major cellular response to chemotherapy in solid tumors and contributes to successful treatment. However, senescent tumor cells are resistant to apoptosis and may also reenter the cell cycle. We set out to find a means to specifically induce senescent tumor cells to undergo cell death and not to reenter the cell cycle that may have general application in cancer therapy.

Experimental Design: We investigated the mechanisms regulating cell survival in drug-induced senescent tumor cells. Using immunofluorescence and flow cytometry–based techniques, we established the status of the ataxia telangiectasia mutated (ATM) signaling pathway in these cells. We assayed the requirement of ATM signaling and p21^CIP1 expression for survival in premature senescent tumor cells using pharmacologic inhibitors and antisense oligonucleotides.

Results: The ATM/ATR (ATM- and Rad3-related) signaling pathway was found to be constitutively active in drug-induced senescent tumor cells. We found that blocking ATM/ATR signaling with pharmacologic inhibitors, including the novel ATM inhibitors KU55933 and CGK733, induced senescent breast, lung, and colon carcinoma cells to undergo cell death. We show that the mechanism of action of this effect is directly via p21^CIP1, which acts downstream of ATM. This is in contrast to the effects of ATM inhibitors on normal, untransformed senescent cells.

Conclusions: Blocking ATM and/or p21^CIP1 following initial treatment with a low dose of senescence-inducing chemotherapy is a potentially less toxic and highly specific treatment for carcinomas.

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