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Clinical Cancer Research Vol. 6, 1073-1078, March 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

DNA-dependent Protein Kinase Activity Correlates with Ku70 Expression and Radiation Sensitivity in Esophageal Cancer Cell Lines1

Heng-Jiang Zhao, Yoshio Hosoi2, Hideo Miyachi, Keiichiro Ishii, Masayuki Yoshida, Kenji Nemoto, Yoshihiro Takai, Shogo Yamada, Norio Suzuki and Tetsuya Ono

Departments of Radiation Research [H-J. Z., Y. H., K. I., M. Y., T. O.] and Radiology [H. M., K. N., Y. T., S. Y.], Tohoku University School of Medicine, Sendai 980-8575, Japan, and Department of Radiation Oncology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan [Y. H., N. S.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We investigated the relationship between DNA-dependent protein kinase (DNA-PK) activity and radiation sensitivity using 14 esophageal cancer cell lines, TE 1–14. DNA-PK activities differed significantly among the cell lines. The highest DNA-PK activity observed in TE-8 was more than two times higher than the lowest DNA-PK activity observed in TE-5. Significant correlation was observed between DNA-PK activity and D0 (r = 0.766; P = 0.0008). Western blots analysis revealed a significant correlation between DNA-PK activity and Ku70 expression, suggesting that the regulation in DNA-PK activity was associated with Ku70 expression. The data suggest that the measurement of DNA-PK activity and/or Ku70 expression may provide a useful way to predict radiation sensitivity.


   INTRODUCTION
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 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
DNA-PK3 is a nuclear protein with serine/threonine kinase activity and occurs as a complex consisting of the DNA-PKcs and a heterodimer of the Ku70 and Ku80 proteins (1) . Ku binds to double-strand ends or to other discontinuities on DNA, and it recruits DNA-PKcs (1) . DNA-PK plays an important role in the repair of DNA DSBs and in V(D)J recombination (2) . Cells lacking DNA-PK activity because of defects in DNA-PK components, such as human malignant glioma M059J cells and cells derived from scid mice, show hypersensitivity to ionizing radiation (2, 3, 4, 5, 6) . A phosphatidylinositol 3-kinase inhibitor, wortmannin, inhibits DNA-PK activity and sensitizes cells to ionizing radiation (7 , 8) .

Prediction of radiation sensitivities of cancer cells is desired to determine therapeutic course before radiation therapy. DNA-PK is a candidate for index of intrinsic cellular radiation sensitivity because of its commitment on DSB repair (9) . Several investigators examined the relationship between DNA-PK activity and radiation sensitivity, but the results are not definitive (10, 11, 12, 13) . On the other hand, it is reported that DNA-PK activity correlates with sensitivities to DNA-damaging agents including radiomimetic agents, such as chlorambucil, neocarcinostatin, mechlorethamine, and Adriamycin (14, 15, 16, 17) .

In the present study, we have examined whether DNA-PK activity correlates with radiation sensitivity of 14 esophageal cancer cell lines and whether DNA-PK activity correlates with expression of Ku70, Ku80, or DNA-PKcs protein. The results show significant correlations between DNA-PK activity and D0 and between DNA-PK activity and Ku70 expression. The data suggest that measurement of DNA-PK activity and/or Ku70 expression may provide a useful way to predict radiation sensitivity.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cells.
Esophageal cancer cell lines TE 1–14 were obtained from the Cancer Cell Repository, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan; Table 1Citation ). TE-3 was established from resected s.c. lymph node metastasis, TE-9 was established from the pleural effusion, and other TE cell lines were established from the resected primary tumors (18) . LM217 is an SV40 transformed human fibroblast cell line derived from HS27 (19) .


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  		Table 1 Origin, radiation sensitivity, and doubling time of esophageal cancer cell lines

 
X-Irradiation and Radiation Sensitivity.
Irradiation was conducted with X-rays generated by a Shimadzu HF-320 apparatus (Shimadzu Mectem, Shiga, Japan) operated at 200 kV and 10 mA with 0.5 mm Cu and 1.0 mm Al filters. The dose rate was 0.72 Gy/min. Eighteen h after subculturing of cells in exponential growth phase, they were irradiated at graded doses (0–8 Gy) and cultured in Petri dishes at 37°C in a 5% CO2 incubator. Two to 4 weeks later, cells were stained with methylene blue, and colonies that consisted of >50 cells were counted.

Doubling Times.
One hundred thousand viable cells were incubated in Petri dishes at 37°C in a 5% CO2 incubator. Cells were treated with 0.25% trypsin and 0.1% EDTA 2, 4, 6, or 8 days after subculturing. Total cell number per dish was counted using the Coulter Counter Model ZBI (Coulter Electronics, Inc., Hialeah, FL). Doubling times were calculated from the growth curves of cultures in the exponential phase of the growth.

Whole-Cell Extracts.
Whole-cell extracts were prepared as described previously (20) . Briefly, after washing with Tris-buffered saline (2 mM Tris, pH 7.2; 150 mM NaCl) two times, cells were suspended in 100 µl of low salt buffer [10 mM HEPES (pH 7.2), 25 mM KCl, 1 mM NaCl, 1.1 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM phenylmethylsulfonyl fluoride, 1 mM DTT, 1 µg/ml pepstatin, 1 µg/ml leupeptin, and 1 µg/ml antipain], frozen in liquid nitrogen, and thawed at 30°C three times. After 60 min incubation at 4°C, the suspension was adjusted to 0.4 M KCl by adding 3.5 M KCl, incubated for 30 min at 4°C, and centrifuged for 10 min at 15,000 rpm. The supernatant was designated as the whole-cell extract. Protein concentrations were determined using the Bio-Rad Protein Assay (Bio-Rad, Hercules, CA).

DNA-PK Activity.
DNA-PK activity was assayed as described previously using a synthetic peptide (EPPLSQEAFADLWKK; Ref. 8 ). The whole-cell extracts were incubated in 20 µl of kinase buffer [20 mM HEPES-NaOH (pH 7.2), 100 mM KCl, 5 mM MgCl2, 1 mM DTT, 0.5 mM NaF, 0.5 mM ß-glycerophosphate, 0.2 mM ATP, 10 µCi/ml [{gamma}-32P]ATP in the presence 0.01 mg/ml sonicated salmon sperm DNA, and 0.5 mg/ml substrate peptide] at 37°C for 15 min. The final protein concentration in the reaction mixture was 37.5 µg/ml. The reactions were stopped by the addition of 20 µl of 30% acetic acid and spotted onto P81 paper discs (Whatman International Ltd., Maidstone, United Kingdom). The discs were washed four times in 15% acetic acid. Radioactivity in the paper discs was measured in a liquid scintillation counter.

Western Blots.
Ten µg of whole-cell extracts were analyzed by electrophoresis on 8% SDS-PAGE for Ku70 and Ku80 and on 6% SDS-PAGE for DNA-PKcs. Then, they were transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA) using a wet transfer unit (Nihon Eido, Tokyo, Japan). The membranes were probed with anti-Ku70 (C19; Santa Cruz Biotechnology, Santa Cruz, CA), anti-Ku80 (C20; Santa Cruz Biotechnology), anti-DNA-PKcs (AHP318; Serotec, Oxford, United Kingdom), or anti-actin (MAB1501; Chemicon International, Inc., Temecula, CA) antibodies. Detection was performed with 125I-labeled protein G (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom). Protein levels of Ku70, Ku80, and DNA-PKcs were measured by a imaging analyzer, BAS2000 (Fuji Photo Film, Tokyo, Japan). Protein levels of Ku70, Ku80, and DNA-PKcs were normalized using that of actin (21) .


   RESULTS
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The histology, tumor stage, and differentiation of the original tumors from which the TE 1–14 cell lines were established are shown in Table 1Citation . The SF2, D0, and Dq values of the esophageal cancer cell lines were determined from the survival curves drawn from the results of at least two independent experiments (Table 1)Citation . We tested the statistical significance of differences in radiation sensitivity among the esophageal cancer cell lines derived from tumors in different stages or different differentiations. There is a significant difference in the SF2 among the cell lines derived from the tumors in different differentiations (P = 0.0473). The average SF2 of the cell lines derived from the-well differentiated tumors were higher than that of the cell lines derived from poorly differentiated tumors (P = 0.0182). No significant correlation was observed between the radiation sensitivity and the stage of the tumors from which the cells were derived. We also tested the statistical significance of the correlation between the doubling time of the 14 cell lines and the D0, Dq, or SF2. No significant correlation was observed between the doubling time and these values.

The DNA-PK activities of the 14 cell lines are shown in Fig. 1Citation . DNA-PK activities are expressed as values relative to that of LM217, which was set to a value of 1. The DNA-PK activities were significantly different among the cell lines (P < 0.0001; Fig. 1Citation ). The highest DNA-PK activity observed in TE-8 was more than two times higher than the lowest DNA-PK activity observed in TE-5 (P < 0.0001; Fig. 1Citation ). All of the mean DNA-PK activities of the esophageal cancer cell lines were higher than that of LM217 (Fig. 1)Citation .



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  		Fig. 1. DNA-PK activities of esophageal cancer cell lines. DNA-PK activities are expressed as values relative to that of LM217, which is set to a value of 1. Whole-cell extracts from LM217 and TE 1–14 were prepared at the same time, and the extract from LM217 was used as control. Data are results from three independent experiments; bars, SD.

 
Next, we tested the statistical significance of the correlation between DNA-PK activity and the D0, Dq, or SF2 (Fig. 2Citation ). A significant correlation was observed between DNA-PK activity and the D0 (r = 0.766, P = 0.0008), which supports a significant linear relationship between DNA-PK activity and the D0 (Y = 0.435 + 0.739X; Fig. 2ACitation ). No significant correlation was observed between DNA-PK activity and the Dq nor between DNA-PK activity and the SF2 (Fig. 2, B and CCitation ).



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  		Fig. 2. Relationship between DNA-PK activity and the D0 (A), Dq (B), or SF2 (C). •, DNA-PK activity. The D0 (A), Dq (B), or SF2 (C) values of the 14 cell lines are shown. A, regression line.

 
The histology of TE-7 was adenocarcinoma, and the histologies of all of the other cell lines were squamous cell carcinoma. To estimate the contribution of the adenocarcinoma cell line TE-7 to the statistical analysis mentioned above, the same statistical analysis was carried out using the 13 squamous cell carcinoma cell lines, except for TE-7. The results were essentially the same, i.e., significant correlation was observed between DNA-PK activity and the D0 (r = 0.802, P = 0.0005).

To determine the relationship between DNA-PK activity and expression of Ku70, Ku80, or DNA-PKcs protein, Western blots of cell extracts probed for Ku70, Ku80, and DNA-PKcs protein were carried out (Fig. 3)Citation . The Mr 460,000 protein was detected in all of the Western blots proved for DNA-PKcs. Degradation products of DNA-PKcs having molecular weights of Mr 240,000, 150,000, and 120,000 were not detected (Ref. 22 ; Fig. 3Citation ). The full-length Ku80 protein was detected in all of the Western blots proved for Ku80 protein, and variant forms of Ku80 protein were not detected (Ref. 14 ; Fig. 3Citation ). A significant correlation was observed between DNA-PK activity and Ku70 expression (r = 0.541, P = 0.046; Fig. 4ACitation ). No significant correlation was observed between DNA-PK activity and expression of Ku80 or DNA-PKcs protein (Fig. 4, B and CCitation ). Next, we tested the statistical significance of the correlation between expression of Ku70, Ku80, or DNA-PKcs protein and the value of D0, Dq, or SF2. A significant correlation was observed between the D0 and Ku70 expression (r = 0.573, P = 0.032).



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  		Fig. 3. Western blots of cell extracts probed for DNA-PKcs, Ku70, Ku80, or {alpha}-actin protein. Lanes 1–14, cell lines TE 1–14.

 


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  		Fig. 4. Relationship between DNA-PK activity and the expression of Ku70 (A), Ku80 (B), or DNA-PKcs (C) protein. A, regression line. Protein levels are expressed as values relative to that of TE-1, which is set to a value of 1.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We used the esophageal cancer cell lines for the following reasons:

(a) DNA-PK plays an important role in DSB repair. However, there are many other proteins related to DSB repair, such as the gene products of ATM, ATR, and the Nijmegen breakage syndrome 1 gene (23, 24, 25, 26) . To reduce fluctuations in the activities of these DSB repair-related proteins, cancer cell lines having the same histology and the same origin were used.

(b) For comparison between DNA-PK activity and cellular radiation sensitivity, D0 should be examined because cells defective in DNA-PK components, such as M059J cells and cells derived from scid mice, are known to have smaller D0s than control cells (3, 4, 5, 6 , 27 , 28) . However, it is difficult to compare the D0 using primary cultures because of contamination with normal fibroblasts.

For these reasons, we examined the relationship between DNA-PK activity and the D0, Dq, or SF2 using esophageal cancer cell lines.

In the present study, a significant correlation was observed between DNA-PK activity and the D0. DNA-PK activity did not correlate with the SF2 or the Dq. Wide shoulders were observed in the shapes of the survival curves for TE 1–14 exposed to ionizing radiation (data not shown), whereas the survival curves for cells derived form scid mice had a narrow shoulder (27) . This might explain why DNA-PK activity did not correlate with the SF2 or Dq in the present study.

Because DNA-PK activity of the esophageal cancer cell lines correlates with the D0 but not with the SF2 or Dq, the DNA-PK activity could be used to predict the radiation sensitivity of tumors if the irradiation dose per fraction were high enough to ignore the difference in the initial slope of the survival curve. However, DNA-PK activity is unlikely to be used as a means to predict the radiation sensitivity during conventional radiotherapy because the irradiation dose per fractionation is usually 1.8–2.4 Gy for conventional radiotherapy. In radiosurgery and intraoperative radiotherapy, 6–50 Gy is used as the dose per fraction. In these cases, DNA-PK activity might be a good means to predict radiation sensitivity.

If DNA-PK activity of tumor cells were correlated with radiation sensitivity, and if DNA-PK activity were higher in tumor cells than in the normal tissue around the tumor, the tumor could be selectively sensitized to radiation by inactivation of DNA-PK activity. A phosphatidylinositol 3-kinase inhibitor, wortmannin, is reported to inhibit DNA-PK activity. However, it can also inhibit the activities of the ATM and ATR proteins (29 , 30) . Chan et al. (31) reported lack of correlation between ATM protein expression and tumor cell radiosensitivity. The wide spectrum of wortmannin’s effects may make it less selective as a agent for radiation sensitization. A selective DNA-PK inhibitor is highly desirable from the clinical point of view for the selective sensitization of tumor cells to ionizing radiation.

The DNA-PK activities of TE 1–14 differ significantly. However, regulation of DNA-PK activity is not well known. Muller and Salles (14) reported that DNA-PK activity was related to the DNA-end binding activity and expression of the Ku70 and Ku80 proteins. Our results show that DNA-PK activity correlates with Ku70 expression, suggesting that DNA-PK activity is regulated by Ku70 expression. For another mechanism of regulation of DNA-PK activity, it has been reported that the expression of variant Ku80 regulates DNA-PK activity in leukemic cells (14) . However, in the present study, variant forms of Ku80 were not detected.

In conclusion, the data presented demonstrate that DNA-PK activity correlates with radiation sensitivity and Ku70 expression, suggesting that: (a) DNA-PK activity can be used as a index of radiation sensitivity; and (b) DNA-PK activity might be regulated by Ku70 expression.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Grant 09255102 from the Ministry of Education, Science, Sports and Culture, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-0033, Japan. Phone: 81-3-5841-3505; Fax: 81-3-3815-4220; E-mail: hosoi{at}m.u-tokyo.ac.jp Back

3 The abbreviations used are: DNA-PK, DNA-dependent protein kinase; DNA-PKcs, DNA-PK catalytic subunit; DSB, double strand break; scid, severe combined immune deficient; ATM,ataxia telangiectasia mutated; ATR,ataxia-telangiectasia and Rad 3-related. Back

Received 9/24/99; revised 12/30/99; accepted 1/ 4/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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