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Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine¹

Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [J. N. S., E. C. B., L. M. K., R. S. T., P. R., R. T. A.], and National Cancer Research Institute, Biology Division, Tokyo, Japan 104-0045 [Y. T.]

Caffeine exposure sensitizes tumor cells to ionizing radiation and other genotoxic agents. The radiosensitizing effects of caffeine are associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints. The similarity of these checkpoint defects to those seen in ataxia-telangiectasia (A-T) suggested that caffeine might inhibit one or more components in an A-T mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells. We now show that caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization. Moreover, like ATM-deficient cells, caffeine-treated A549 lung carcinoma cells irradiated in G₂ fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit - and UV radiation-induced phosphorylation of p53 on Ser¹⁵, a modification that may be directly mediated by the ATM and ATR kinases. DNA-dependent protein kinase, another ATM-related protein involved in DNA damage repair, was resistant to the inhibitory effects of caffeine. Likewise, the catalytic activity of the G₂ checkpoint kinase, hChk1, was only marginally suppressed by caffeine but was inhibited potently by the structurally distinct radiosensitizer, UCN-01. These data suggest that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ATM and ATR and that both proteins are relevant targets for the development of novel anticancer agents.

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				R. Sakasai, K. Shinohe, Y. Ichijima, N. Okita, A. Shibata, K. Asahina, and H. Teraoka Differential involvement of phosphatidylinositol 3-kinase-related protein kinases in hyperphosphorylation of replication protein A2 in response to replication-mediated DNA double-strand breaks Genes Cells, March 1, 2006; 11(3): 237 - 246. [Abstract] [Full Text] [PDF]

				S. J. H. Arlander, S. J. Felts, J. M. Wagner, B. Stensgard, D. O. Toft, and L. M. Karnitz Chaperoning Checkpoint Kinase 1 (Chk1), an Hsp90 Client, with Purified Chaperones J. Biol. Chem., February 3, 2006; 281(5): 2989 - 2998. [Abstract] [Full Text] [PDF]

				T. Hiyama, M. Katsura, T. Yoshihara, M. Ishida, A. Kinomura, T. Tonda, T. Asahara, and K. Miyagawa Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells Nucleic Acids Res., February 2, 2006; 34(3): 880 - 892. [Abstract] [Full Text] [PDF]

				Y. Seo, T. Yan, J. E. Schupp, K. Yamane, T. Radivoyevitch, and T. J. Kinsella The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine Cancer Res., January 1, 2006; 66(1): 490 - 498. [Abstract] [Full Text] [PDF]

				R. A. Greenberg, B. Sobhian, S. Pathania, S. B. Cantor, Y. Nakatani, and D. M. Livingston Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes Genes & Dev., January 1, 2006; 20(1): 34 - 46. [Abstract] [Full Text] [PDF]

				W. Zhang, L. Fletcher, and R. J. Muschel The Role of Polo-like Kinase 1 in the Inhibition of Centrosome Separation after Ionizing Radiation J. Biol. Chem., December 30, 2005; 280(52): 42994 - 42999. [Abstract] [Full Text] [PDF]

				G. I. Terzoudi, K. N. Manola, G. E. Pantelias, and G. Iliakis Checkpoint Abrogation in G2 Compromises Repair of Chromosomal Breaks in Ataxia Telangiectasia Cells Cancer Res., December 15, 2005; 65(24): 11292 - 11296. [Abstract] [Full Text] [PDF]

				Y. Lubelsky, N. Reuven, and Y. Shaul Autorepression of Rfx1 Gene Expression: Functional Conservation from Yeast to Humans in Response to DNA Replication Arrest Mol. Cell. Biol., December 1, 2005; 25(23): 10665 - 10673. [Abstract] [Full Text] [PDF]

				C.-G. Jung, H.-J. Kim, M. Kawaguchi, K. K. Khanna, H. Hida, K. Asai, H. Nishino, and Y. Miura Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation Development, December 1, 2005; 132(23): 5137 - 5145. [Abstract] [Full Text] [PDF]

				P. Lebrun, M. R. Montminy, and E. Van Obberghen Regulation of the Pancreatic Duodenal Homeobox-1 Protein by DNA-dependent Protein Kinase J. Biol. Chem., November 18, 2005; 280(46): 38203 - 38210. [Abstract] [Full Text] [PDF]

				K. Okamoto, K. Kashima, Y. Pereg, M. Ishida, S. Yamazaki, A. Nota, A. Teunisse, D. Migliorini, I. Kitabayashi, J.-C. Marine, et al. DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation Mol. Cell. Biol., November 1, 2005; 25(21): 9608 - 9620. [Abstract] [Full Text] [PDF]

				A. Tyagi, R. P. Singh, C. Agarwal, S. Siriwardana, R. A. Sclafani, and R. Agarwal Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells Carcinogenesis, November 1, 2005; 26(11): 1978 - 1987. [Abstract] [Full Text] [PDF]

				P. Kramata, Y.-P. Lu, Y.-R. Lou, J. L. Cohen, M. Olcha, S. Liu, and A. H. Conney Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice Carcinogenesis, November 1, 2005; 26(11): 1965 - 1974. [Abstract] [Full Text] [PDF]