Histone H2AX Phosphorylation as a Predictor of Radiosensitivity and Target for Radiotherapy

Based on the role of phosphorylation of the histone H2A variant H2AX in recruitment of DNA repair and checkpoint proteins to the sites of DNA damage, we have investigated γH2AX as a reporter of tumor radiosensitivity and a potential target to enhance the effectiveness of radiation therapy. Clinically relevant ionizing radiation (IR) doses induced similar patterns of γH2AX focus formation or immunoreactivity in radiosensitive and radioresistant human tumor cell lines and xenografted tumors. However, radiosensitive tumor cells and xenografts retained γH2AX for a greater duration than radioresistant cells and tumors. These results suggest that persistence of γH2AX after IR may predict tumor response to radiotherapy. We synthesized peptide mimics of the H2AX carboxyl-terminal tail to test whether antagonizing H2AX function affects tumor cell survival following IR. The peptides did not alter the viability of unirradiated tumor cells, but both blocked induction of γH2AX foci by IR and enhanced cell death in irradiated radioresistant tumor cells. These results suggest that H2AX is a potential molecular target to enhance the effects of radiotherapy. Based on the role of phosphorylation of the histone H2A variant H2AX in recruitment of DNA repair and checkpoint proteins to the sites of DNA damage, we have investigated γH2AX as a reporter of tumor radiosensitivity and a potential target to enhance the effectiveness of radiation therapy. Clinically relevant ionizing radiation (IR) doses induced similar patterns of γH2AX focus formation or immunoreactivity in radiosensitive and radioresistant human tumor cell lines and xenografted tumors. However, radiosensitive tumor cells and xenografts retained γH2AX for a greater duration than radioresistant cells and tumors. These results suggest that persistence of γH2AX after IR may predict tumor response to radiotherapy. We synthesized peptide mimics of the H2AX carboxyl-terminal tail to test whether antagonizing H2AX function affects tumor cell survival following IR. The peptides did not alter the viability of unirradiated tumor cells, but both blocked induction of γH2AX foci by IR and enhanced cell death in irradiated radioresistant tumor cells. These results suggest that H2AX is a potential molecular target to enhance the effects of radiotherapy. Radiotherapy (RT) 1The abbreviations used are: RT, radiotherapy; UnphosP, unphosphorylated H2AX tail peptide; PhosP, phosphorylated H2AX tail peptide; DAPI, 4′,6-diamidino-2-phenylindole; IR, ionizing radiation; MEF, mouse embryo fibroblast; Gy, Gray; PI, propidium iodide. remains an important form of local and regional cancer therapy. Approximately 50-70% of all cancer patients receive RT during their treatment. Advances in tumor imaging and physical targeting of ionizing radiation (IR) (1.Webb S. Lancet Oncol. 2000; 1: 30-36Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 2.Suit H. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 798-809Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) and optimization of IR delivery schedules from single treatments to continuous irradiation have yielded significant improvements in patient outcome. Nonetheless, many tumors are poorly controlled by RT alone. Two major strategies to enhance the effects of IR have offered clinical benefit. The use of cytotoxic chemotherapy as a radiosensitizer (3.Vokes E.E. Haraf D.J. Brockstein B.E. Weichselbaum R.R. Semin. Radiat. Oncol. 1999; 9: 70-76PubMed Google Scholar) is based on the rationale that additional DNA damage may lower the threshold of cell death by IR. As a second approach, biological targeting (4.Mundt A.J. Roeske J.C. Weichselbaum R.R. Bast R.C. Kufe D.W. Pollock R.E. Weichselbaum R.R. Holland J.F. Frei E. Cancer Medicine. 5th Ed. B. C. Decker, Hamilton, Canada2000: 465-478Google Scholar, 5.Milas L. Mason K.A. Liao Z. Ang K.K. Head Neck. 2003; 25: 152-167Crossref PubMed Scopus (95) Google Scholar) antagonizes physiological survival mechanisms of tumors. Current biological strategies include use of angiogenesis inhibitors (6.Mauceri H.J. Hanna N.N. Beckett M.A. Gorski D.H. Staba M.J. Stellato K.A. Bigelow K. Heimann R. Gately S. Dhanabal M. Soff G.A. Sukhatme V.P. Kufe D.W. Weichselbaum R.R. Nature. 1998; 394: 287-291Crossref PubMed Scopus (656) Google Scholar, 7.Abdollahi A. Lipson K.E. Han X. Krempien R. Trinh T. Weber K.J. Hahnfeldt P. Hlatky L. Debus J. Howlett A.R. Huber P.E. Cancer Res. 2003; 63: 3755-3763PubMed Google Scholar), hormonal blockade (8.D'Amico A.V. Schultz D. Loffredo M. Dugal R. Hurwitz M. Kaplan I. Beard C.J. Renshaw A.A. Kantoff P.W. JAMA (J. Am. Med. 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H2AX of W. and by In all protein of the by after to or by on for in in and γH2AX and or Inc., as on an a San to and as for γH2AX foci or of of a of cells for each of BRCA1 from to human H2AX in their unphosphorylated and phosphorylated synthesized and in at and cells to the to to the of or tumor cells a peptide yielded cells cells IR as at for and for as of cells after IR imaging to propidium of H2AX in used radioresistant and radiosensitive human cell cell lines R.R. W. Beckett M. T. D. J. Natl. Sci. U. S. A. PubMed Scopus Google Scholar) to the between radiation and γH2AX focus formation over the relevant range from to we the radiosensitivity of and by as by loss of propidium and survival by a formation after Gy, of cells and of cells for whereas after Gy, increased to of and of cells Despite differences in IR cell death in both and We these of cell death the of γH2AX foci following IR exposure and after Gy, of γH2AX foci of cells Gy, of and of γH2AX in of both cell at and γH2AX immunoreactivity also increased IR in both and cells. These that induction of γH2AX foci is IR and suggest that γH2AX is an of survival and induction of We the of H2AX phosphorylation in and cells after the relevant of of and of viability by after Gy, of and of cells retained γH2AX but the of cells foci foci in of cells and of cells. foci in of but retained in of the of cells foci to whereas at for of γH2AX in the cell for and for of γH2AX for the of γH2AX foci cell the between γH2AX and radiosensitivity in human tumor cells, we induction and loss of γH2AX from and cell lines from a single human cell survival following radiation as by and survival Beckett M.A. Weichselbaum R.R. J. Res. 1995; Full Text PDF PubMed Scopus Google Scholar). induced γH2AX foci to a similar in each cell but the of γH2AX focus after IR, of the relatively radioresistant cells γH2AX whereas of retained all cells of whereas of We γH2AX in and human cell lines that in radiosensitivity M.E. D. M. J.F. Natl. Sci. U. S. A. PubMed Scopus Google Scholar). A. Beckett and R. R. induced γH2AX in of and of cells at of radioresistant cells of radiosensitive cells of γH2AX foci might H2AX and/or from phosphorylated and cell and after by H2AX immunoreactivity by loss of γH2AX However, H2AX protein did not in the following IR not also in based on and of tumors after IR. A. Beckett and R. R. we γH2AX after irradiation of tumors in tissue and after Gy, and by induced γH2AX in both and immunoreactivity from tumors but in the tumors. these results that the of of γH2AX foci and/or immunoreactivity the radiosensitivity of human tumor cells and γH2AX after the of doses of IR on γH2AX in a for we γH2AX in and cells a single or of at a single of and of cells form in a survival of or cells induced foci in of cells, results the of cells foci of cells and of retained γH2AX foci after Gy, γH2AX foci in of and of cells. doses at and enhanced the differences in and persistence of γH2AX foci between and a and The initial survival to However, the second and doses on of and similar in the of not In cells, γH2AX foci similar after each that by of cells cell survival by each that after the Gy, and and the second and the of cells increased over the after the of cells retained The and of foci in cells also increased during the not of and cell similar of γH2AX immunoreactivity after the single In the a cells a γH2AX immunoreactivity after the second or γH2AX after each in the cells. after the γH2AX in greater than in H2AX γH2AX and BRCA1 on mouse A. Petersen S. Romanienko P.J. Fernandez-Capetillo O. Chen H.T. Sedelnikova O.A. B. E. M.J. Redon C. Pilch D.R. A. M. Camerini-Otero R.D. L. K. Bonner W.M. Nussenzweig M.C. Nussenzweig A. 2002; PubMed Scopus Google Scholar, J. H. S.R. J.C. C. K. R. Natl. Sci. U. S. A. 2002; PubMed Scopus Google Scholar), we that the from DNA damage to H2AX phosphorylation might recruitment and of repair and checkpoint thereby human tumor cells to IR. As an initial approach, we peptide mimics of the unphosphorylated and phosphorylated of the H2AX carboxyl-terminal tail as of H2AX for phosphorylation by kinases or to approach, we M.C. J. J. G. Nat. 2001; PubMed Scopus Google Scholar) H2AX tail and peptides and the cells for response to IR. that both and peptides cells, the peptides a and these of nuclear and both and after irradiation cells alone or a peptide and irradiated Gy, the However, H2AX tail peptide to the blocked the formation of γH2AX foci cell by IR increased following of the tail H2AX tail peptide survival after alone PhosP, H2AX has been to recruitment of DNA repair proteins to double breaks A. Fernandez-Capetillo O. Kruhlak M.J. Pilch D.R. Staudt D.W. Lee A. Bonner R.F. Bonner W.M. Nussenzweig A. Nat Cell Biol. 2003; 5: 675-679Crossref PubMed Scopus (815) Google Scholar, Rogakou E.P. M. Bonner W.M. Curr. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). whether the H2AX tail peptides may the recruitment of a DNA repair protein to DNA double strand we the of BRCA1 in BRCA1 foci in irradiated but in of the and H2AX tail these suggest that H2AX tail peptides may enhance cell death by DNA repair and/or checkpoint these we the tail peptides and human tumor cells. the and H2AX tail peptides blocked of γH2AX foci after Importantly, the H2AX tail peptides increased in both the and cells and However, the induction of in cells following all IR doses greater than in cells. the survival of radioresistant cells following by both H2AX tail peptides PhosP, the radiosensitive cells a loss of survival after H2AX of IR to the clinical between tumor the in curability tumors to DNA damage a understanding of the of to predict and tumor response As an initial approach, we the of γH2AX induction by relevant doses as a potential of tumor We a between radiosensitivity and the of γH2AX in human tumor cell lines and xenografted tumor a cell from a and cancer γH2AX foci a than a radiosensitive tumor cell similar in other pairs of radioresistant and radiosensitive human tumor cell by after a single radioresistant cell lines γH2AX whereas the radiosensitive cells We whether the γH2AX might suggest DNA the delivery of doses at both the differences in γH2AX and loss of viability between the radioresistant and radiosensitive tumor cells. It is relevant to that similar and doses are used in RT, γH2AX as a for of therapy. of γH2AX after RT might a of tumor radiosensitivity in therapy. γH2AX by might in radiation and/or delivery to each The between γH2AX and cell survival suggested a H2AX phosphorylation not DNA damage but mediates its test we synthesized peptide mimics of the H2AX carboxyl-terminal tail as of H2AX function in cells, as a of peptide blocked the formation of γH2AX and BRCA1 foci and cell death after IR. We that these peptides may H2AX for phosphorylation by ATM/ATR family kinases and/or for to DNA repair and checkpoint the peptides may the of a of DNA repair proteins at DSBs for repair of similar in the human tumor cell the response of the radioresistant cell The H2AX peptides to a in IR-induced at doses from to In a of cell survival after or H2AX peptides a loss of tumor cells, have a apoptotic response to IR by the peptide in both tumors that a apoptotic after IR greater radiation the of to the of human tumors remains (13.Meyn R.E. Stephens L.C. Milas L. Cancer Metastasis Rev. 1996; 15: 119-131Crossref PubMed Scopus (79) Google Scholar, 14.Roninson I.B. Broude E.V. Chang B.D. Drug Resist. Update. 2001; 4: 303-313Crossref PubMed Scopus (621) Google Scholar). Nonetheless, modulating IR-induced via H2AX tail peptides might a for radioresistant tumors. results of the that H2AX may in radiotherapy. the of cytotoxic used in M.A. D.G. Semin. Radiat. Oncol. 2003; 13: PubMed Scopus Google Scholar), targeting H2AX may have effects on unirradiated DNA double strand breaks limited to the tumor via physical targeting of biological targeting H2AX may a to We the of and other of the Weichselbaum and and their and

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