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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas and 2 Department of Cell Biology and Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga, Japan
Requests for reprints: Yasuko Kondo, Department of Neurosurgery, Unit 64, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-4045; Fax: 713-794-5514; E-mail: yaskondo{at}mdanderson.org.
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Abstract |
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Introduction |
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IR induces DNA double-strand breaks, which are the most lethal form of damage to DNA. In mammals, DNA double-strand breaks are generally repaired via nonhomologous end joining, in which DNA-dependent protein kinase (DNA-PK), a nuclear serine-threonine protein kinase, plays a key role (3–5). DNA-PK is composed of a catalytic subunit (DNA-PKcs) and a DNA-binding heterodimer consisting of Ku70 and Ku80. Ku binds to both ends of a double-strand break and recruits DNA-PKcs to the DNA end. Then, DNA-PK allows DNA ligase IV and X-ray cross-complementing 4 (XRCC4) to complete DNA repair (5).
In addition to its role in DNA repair, DNA-PK is also involved in apoptosis (4). When IR causes double-strand breaks, the DNA-PK complex senses and repairs them; however, when DNA damage is excessive, DNA-PK induces apoptosis. Typically, IR induces apoptosis by activating p53, Bax, and caspases, although p53-independent apoptosis has also been reported (6). Recently, another type of programmed cell death, autophagy, has been reported. Autophagic cell death is characterized by the prominent formation of double-membrane structures, called autophagosomes, in the cytoplasm, whereas the nucleus remains predominantly intact (7, 8). Autophagosomes are multiple-membrane structures often containing subcellular organelles, such as mitochondria (7). The cytoskeleton is well preserved until the late stage. On the other hand, in apoptotic cells, the nucleus is condensed or fragmented and the cytoskeleton is degraded from an early stage of cell death. We and others reported that IR at high doses induces autophagy in some types of cancer cells, including malignant glioma cells (9, 10). However, the relationship between DNA-PK and IR-induced autophagy is poorly defined.
In the present study, we used human malignant glioma M059J and M059K cells to assess the role of DNA-PK in IR-induced cell death. Although derived from the same malignant glioma specimen as M059K cells, M059J cells lack DNA-PKcs and are sensitive to radiation, whereas M059K cells express DNA-PKcs at a normal level and are resistant to the effects of radiation (11, 12). Therefore, M059J and M059K offer a useful model in which to study the role of DNA-PKcs in radiation-induced DNA damage. Reversal of the radiation-sensitive phenotype was confirmed by introducing into M059J cells a fragment of human chromosome 8, which contains a copy of the DNA-PKcs gene (13). We found that a low dose of IR induced massive autophagic cell death in M059J cells, but only occasional apoptotic cells were detected among M059K cells. Specific inhibition of DNA-PKcs in M059K cells induced autophagy and radiosensitized the cells. Next, we investigated whether the specific inhibition of DNA-PKcs radiosensitizes other malignant glioma cell lines expressing DNA-PKcs (such as U373-MG and T98G). Both tumor cells were sensitized to IR by inducing autophagy. To the best of our knowledge, this is the first study showing that the loss of DNA-PKcs plays an important role in IR-induced autophagy. Our results suggest that this novel form of radiosensitization induces autophagy in malignant gliomas.
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Materials and Methods |
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Ionizing radiation, clonogenic survival, and cell viability assay. Malignant glioma cells were irradiated with a 137Cs-irradiater (Model E-0103, U.S. Nuclear Corp., Burbank, CA) at a dose rate of 3.312 Gy/min. For a clonogenic survival assay, cells irradiated with various doses were seeded in six-well plates, incubated at 37°C for 14 days, and then fixed with ethanol. Cells were stained with 0.5% crystal violet (Sigma, St. Louis, MO) and colonies that contained 
50 cells were counted. The cytotoxic effect of IR for a short term was determined by a trypan blue dye exclusion assay as described previously (14). Tumor cells (1 x 104-2 x 104 cells/well) were seeded in 96-well, flat-bottomed plates after irradiation. One to three days after irradiation, cells were detached by trypsinization and the number of viable cells was counted. The viability of untreated cells was regarded as 100%.
Detection of apoptosis. Nuclei were stained with Hoechst 33258 (Sigma) to detect chromatin condensation or nuclear fragmentation, which are characteristic of apoptosis, as described previously (15). Treated tumor cells were fixed with 4% paraformaldehyde and stained with 0.5 µg/mL Hoechst 33258 for 15 minutes. Two hundred cells were counted under a fluorescence microscope and the incidence of apoptotic cells was scored.
Detection and quantification of acidic vesicular organelles with acridine orange staining. Acidic vesicular organelles were stained with acridine orange as described previously (9, 16). In acridine orange–stained cells, the cytoplasm and nucleus fluoresce bright green and dim red, whereas acidic compartments fluoresce bright red. The intensity of the red fluorescence is proportional to the degree of the acidity and volume of acidic vesicular organelles. Therefore, we can measure the extent of acidic vesicular organelles formation with red fluorescence of acridine orange staining. Tumor cells were stained with 1 µg/mL acridine orange for 15 minutes. Samples were then examined under a fluorescence microscope. Acridine orange labels acidic vesicular organelles, such as autophagosomes (9, 10). A typical acridine orange–positive cell exhibits granular distribution of acridine orange in the cytoplasm, indicative of autophagosome formation. To quantify the development of acidic vesicular organelles, cells were stained with acridine orange for 15 minutes, removed from the plate with trypsin-EDTA (Invitrogen), and collected for the FACScan (Becton Dickinson, San Jose, CA) by using CellQuest software (Becton Dickinson).
Electron microscopy. Malignant glioma cells, grown on gelatinized plastic coverslips, were fixed for 2 hours with 2.5% glutaraldehyde (EM Science, Hatfield, PA) in 0.1 mol/L cacodylate buffer (pH 7.4), postfixed in 1% OsO4 in the same buffer, and then analyzed by electron microscopy as described previously (16). Representative areas were chosen for ultrathin sectioning and viewed with a Hitachi 7600 electron microscope.
Transfection. The green fluorescent protein (GFP) and microtubule-associated protein 1 light chain 3 (LC3) fusion vector (GFP-LC3) was kindly provided by Drs. N. Mizushima and T. Yoshimori (National Institute for Basic Biology, Okazaki, Japan; ref. 17). LC3, the homologue of the yeast Apg 8/Aut7p gene, localizes on the autophagosomal membrane during autophagy (17, 18). We used the GFP-LC3 fused protein to detect autophagy. A ß-galactosidase expression vector (Invitrogen) was used as the control. The sequence of antisenses against DNA-PKcs mRNA was 5'-ACACCGGCTCCGGAGCCCGCCAT-3' (19), and we used the sense of DNA-PKcs, 5'-ATGGCGGGCTCCGGAGCCGGTGT-3', as a control. FuGENE6 Transfection Reagent (Roche, Indianapolis, IN) was used according to manufacturer's instructions. The expression vector or antisense was transfected 24 hours before irradiation.
Western blotting. To detect the expression of ribosomal protein S6 kinase (p70S6K) and p70S6K that is phosphorylated at Thr389, soluble protein for Western blotting was harvested from treated tumor cells lysed in extraction buffer. Equal amounts of protein (40 µg) were separated by SDS-PAGE (7.5% gel; Bio-Rad, Richmond, CA) and transferred to a Hybond-P membrane (Amersham, Co., Piscataway, NJ). The membranes were treated with antibodies against p70S6K and phosphorylated p70S6K (Thr389; Cell Signaling, Beverly, MA) and subjected to Western blotting using an ECL-plus chemiluminescence reagent (Amersham).
DNA-dependent protein kinase activity assay. Whole-cell extracts were prepared using a modification of the method of Finnie et al. (20). Briefly, tumor cells were harvested and washed with PBS. Cell pellets were frozen at –80°C and resuspended in extraction buffer (20 mmol/L HEPES, 450 mmol/L NaCl, 50 mmol/L NaF, 25% v/v glycerol) with Complete protease inhibitor tablets (Roche). The swollen cells were disrupted by incubation alternatively on dry ice and at 30°C (three times) for 1 minute each. After microcentrifugation for 10 minutes at 4°C, supernatants were stored at –80°C before use. The SignaTECT DNA-PK assay system (Promega, Madison, WI) was used to measure DNA-PK activity according to the manufacturer's instructions. [
-32P]ATP was purchased from Perkin-Elmer (Boston, MA). Reactions were analyzed with a scintillation counter.
Senescence detection. Cells were stained with senescence-associated ß-galactosidase by using the Senescence Detection kit (BioVision Research Products, Mountain View, CA).
Statistical analysis. The data were expressed as mean ± SD. Statistical analysis was done by using Student's t test (two-tailed). The criterion for statistical significance was taken as P < 0.05.
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Results |
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10 times higher on M059J cells than on M059K cells (the survival rates of the M059J and M059K cells were 3.9% and 39.1%, respectively). To assess the killing effect of 2 Gy radiation in the short term, we did a cell viability assay up to 3 days after irradiation. The viability of M059J and M059K cells decreased to 44.4% and 92.6%, respectively, after 3 days (Fig. 1B). These results are consistent with previous reports that M059J cells are 10-fold more sensitive to IR than are M059K cells (11, 12).
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To quantify autophagic vacuoles or autophagosomes, we transfected M059J cells with GFP-LC3 fusion plasmid and detected the distribution of LC3 (17). This is one of the specific methods for detecting autophagy (21). In nontreated cells, LC3 was homogeneously distributed in the cytoplasm (Fig. 3D). After 2 Gy irradiation, LC3 was distributed on punctate structures and GFP-LC3 dots were seen in some M059J cells (Fig. 3D). The percentage of M059J cells with GFP-LC3 dots increased significantly from 5.2% to 15.0% after IR (P = 0.0048; Fig. 3E).
Because autophagy is generally regulated by the mammalian target of rapamycin (mTOR) and its downstream p70S6K (22), we examined whether IR affects this pathway in M059J cells. The expression of phosphorylated p70S6K at position Thr389 was strikingly reduced to an undetectable level 1 hour after 2 Gy irradiation in M059J cells but not in M059K cells (Fig. 3F). The expression level of total p70S6K did not change in both cell types. These results collectively indicated that 2 Gy irradiation suppresses the mTOR pathway and induces autophagic cell death in M059J cells but not in M059K cells.
Inhibition of the catalytic subunit of DNA-dependent protein kinases radiosensitizes M059K cells by inducing autophagic cell death. Next, we investigated whether inhibition of DNA-PKcs radiosensitizes M059K cells by inducing autophagy. We used antisense oligonucleotides against DNA-PKcs (AS-DNA-PKcs) to inhibit DNA-PKcs specifically (19). A DNA-PK activity assay showed that treatment with AS-DNA-PKcs (300 nmol/L) for 24 hours inhibited 53% of DNA-PK activity in M059K cells, whereas no significant inhibition was detected in M059K cells treated with 300 nmol/L sense oligonucleotides against DNA-PKcs (S-DNA-PKcs) for 24 hours (Fig. 4A). A clonogenic survival assay revealed that the treatment with AS-DNA-PKcs sensitized M059K cells to IR (Fig. 4B). Moreover, a cell viability assay showed that AS-DNA-PKcs decreased the viability of M059K cells to 60% of that of untreated or S-DNA-PKcs–treated cells 2 and 3 days after 2 Gy irradiation (Fig. 4C). We detected autophagic change with acridine orange staining. The proportion of acridine orange–positive cells increased from 7.7% to 16.3% among M059K cells treated with AS-DNA-PKcs (Fig. 4D). We did electron microscopy to further confirm the induction of autophagic changes. Three days after the treatment with radiation plus AS-DNA-PK, M059K cells showed increased formation of autophagic vacuoles that contained lamellar structures or residual digested material (Fig. 4E-b). These results indicate that AS-DNA-PK radiosensitizes M059K cells by increasing autophagic cell death.
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Discussion |
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Some types of cancer cells exhibit autophagic changes after treatments with IR and chemotherapeutic drugs (7, 9, 10, 24–26). Autophagy begins with the sequestering of cytosolic components, often including intracellular organelles within double-membrane structures. The vacuoles formed in this way are called autophagosomes (22, 27). As autophagosomes mature, their contents acidify. Finally, autophagosomes fuse with lysosomes and their contents are degraded by lysosomal hydrolases. The regulation of autophagy by molecular mechanisms and genes has been extensively studied in yeast. More than 10 autophagy-associated genes (Aut/Apg) that are essential in the autophagic process have been discovered (22). Homologues of some of these genes have been identified in mammals. For example, mTOR regulates many APG genes, including APG1, APG13, and APG17, and inhibits autophagy. Beclin1, a Bcl-2–interacting protein structurally similar to Apg6, induces autophagy. Another group of APG genes is associated with the formation of autophagosomes. The Apg12-Apg5 conjugate localizes to the autophagosome precursors in an Apg7-dependent manner. As the membrane develops, LC3, a homologue of Apg8/Aut7p, is recruited to the membrane. Upon the complete formation of the autophagosome, the Apg12-Apg5 conjugate detaches from it, whereas LC3 remains associated with the membrane (28). Because the localization of LC3 to the autophagosomal membrane is highly specific to autophagy, it can be used to detect autophagy (17, 21).
In the present study, we used the GFP-LC3 fused protein to detect autophagy and showed its localization to the punctate structures (i.e., autophagosomes; Fig. 4). It has been proposed that autophagy leads cancer cells in one of two opposite directions (29). One direction leads to survival, by sequestering toxic materials or recycling proteins (9, 10). The other leads to death by responding to environmental stress. Recently, we identified that Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is associated with autophagic cell death caused by ceramide (24). We have more recently obtained evidence that BNIP3 is up-regulated in M059J cells after treatment with IR (data not shown), presumably mediating autophagic cell death.
DNA-PKcs is a member of the phosphatidylinositol 3-kinase–like family (3). The members of this family have a catalytic domain that has a homologue to phosphatidylinositol 3-kinase but do not phosphorylate lipids. Other members of the phosphatidylinositol 3-kinase–like family are ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and mTOR. ATM and ATR are associated with the control of cell cycle checkpoints in response to DNA damage (30). mTOR is a modulator of autophagy. The targets that DNA-PKcs phosphorylates include DNA-PKcs (31), both Ku subunits (32), XRCC4 (33), p53 (34), MDM2 (35), and c-Abl (36). The phosphorylation of DNA-PKcs, Ku subunits, and XRCC4 is associated with DNA repair, whereas that of p53, MDM2, and c-Abl induces apoptosis. The different roles played by these targets are, therefore, consistent with the notion that DNA-PK has dual roles in DNA damage: one is to sense DNA damage and repair it and the other is to induce apoptosis (4). Specifically, in response to DNA damage, the cell first tries to repair the damage and survive. However, if the cell cannot repair the damage, it undergoes apoptosis and avoids passing damaged DNA to its progeny cells. However, DNA damage does not induce apoptosis in DNA-PKcs–/– cells (37, 38). In accordance with this theory, we did not detect apoptosis in M059J cells after treatment with IR. It is intriguing that the cell death in irradiated M059J cells was due to autophagy. In contrast, we detected some apoptotic cells in M059K cells after they received IR, but most of the cells survived. When DNA-PKcs was inhibited in M059K cells and other malignant glioma cells, autophagy instead of apoptosis was induced. Furthermore, we showed that the mTOR/p70S6K pathway was suppressed by IR and autophagy was induced in M059J cells. Thus, it is tempting to speculate that DNA-PKcs plays a key role not only in the induction of apoptosis but also in the inhibition of autophagy. However, more studies are needed to support that conclusion.
Recently, several studies have focused on inhibiting DNA-PK specifically and sensitizing cancer cells to IR or anticancer drugs. Some investigators used antisense oligonucleotides and small interfering RNA designed to inhibit DNA-PKcs (19, 39, 40). Others used antisense oligonucleotides or peptide to inhibit Ku70 and Ku80 (41–43). Inhibiting one of these components of the DNA-PK complex resulted in the inhibition of DNA double-strand break repair and the radiosensitization of cells. These results are in accordance with the observations in DNA-PK knockout cells: DNA-PKcs–/–, Ku70–/–, and Ku80–/– cells are all hypersensitive to IR (44–46). In the present study, we also showed that using AS-DNA-PKcs to specifically inhibit DNA-PKcs sensitized human malignant glioma M059K, U373-MG, and T98G cells to low-dose IR by inducing autophagy. The inhibition of DNA-PK activity was less in U373-MG and T98G cells than that in M059K cells. Interestingly, induction of autophagy paralleled to the extent of the inhibition of DNA-PK activity. Additionally, other mechanisms, such as apoptosis or senescence, was not detected in U373-MG and T98G cells, indicating that the induction of autophagy is only causative mechanism detected in this study for radiosensitization by AS-DNA-PKcs.
In summary, we showed that IR induces autophagic cell death in DNA-PKcs–deficient M059J cells. The inhibition of DNA-PKcs by using AS-DNA-PKcs induced autophagy and sensitized DNA-PKcs–proficient M059K cells to IR. AS-DNA-PKcs also radiosensitized other malignant glioma cells by inducing autophagy. Such radiation-induced autophagy may enhance the effect of cancer therapies.
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Acknowledgments |
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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 the 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Drs. Tamotsu Yoshimori and Noboru Mizushima for their kind gifts of vectors; Dr. Raymond Meyn for critical reading of this manuscript; and Dr. Anupama Munschi for her technical help.
Received 11/24/04. Revised 2/ 3/05. Accepted 2/25/05.
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