Mapping of oxidative stress responses of human tumor cells following photodynamic therapy using hexaminolevulinate
© Cekaite et al; licensee BioMed Central Ltd. 2007
Received: 20 December 2006
Accepted: 13 August 2007
Published: 13 August 2007
Photodynamic therapy (PDT) involves systemic or topical administration of a lesion-localizing photosensitizer or its precursor, followed by irradiation of visible light to cause singlet oxygen-induced damage to the affected tissue. A number of mechanisms seem to be involved in the protective responses to PDT, including activation of transcription factors, heat shock proteins, antioxidant enzymes and apoptotic pathways.
In this study, we address the effects of a destructive/lethal hexaminolevulinate (HAL) mediated PDT dose on the transcriptome by using transcriptional exon evidence oligo microarrays. Here, we confirm deviations in the steady state expression levels of previously identified early defence response genes and extend this to include unreported PDT inducible gene groups, most notably the metallothioneins and histones. HAL-PDT mediated stress also altered expression of genes encoded by mitochondrial DNA (mtDNA). Further, we report PDT stress induced alternative splicing. Specifically, the ATF3 alternative isoform (deltaZip2) was up-regulated, while the full-length variant was not changed by the treatment. Results were independently verified by two different technological microarray platforms. Good microarray, RT-PCR and Western immunoblotting correlation for selected genes support these findings.
Here, we report new insights into how destructive/lethal PDT alters the transcriptome not only at the transcriptional level but also at post-transcriptional level via alternative splicing.
Photodynamic therapy (PDT) combines a light-activated drug with non-thermal light to cause selective damage to the target tissue . The major mechanism of action of PDT has been shown to be induction of oxidative stress [2, 3]. It has also been shown that PDT-mediated oxidative stress induces a transient increase in the early response genes FOS, JUN, MYC, and EGR1 [4, 5], heat shock proteins (HSPs) [6–9], as well as SOD2, LUC7A, CASP8, and DUSP1 . Furthermore, relevant information exists regarding specific gene expression patterns regulated by oxidative stress [5, 11–18]. Signaling pathways influenced by PDT have not been fully elucidated, although a number of studies have addressed this issue [5, 10, 19]. Moreover, relatively little is known regarding global gene activity, particularly when oxidative stress becomes excessive, as is the case for PDT. Both clonogenic survival of cells from tumors after in vivo PDT treatment  and resistance to aminolevulinic acid (ALA)-mediated PDT  have been reported previously. Intrinsic cell sensitivity to PDT has been proposed  to be an important component in the mechanism that leads to tumor response following PDT treatment in vivo.
A better understanding of the mechanics of the destructive PDT could facilitate further the development of this therapy. Oxidative stress evokes many intracellular events including apoptosis . Modulating the anti-apoptosis factors that are activated by survival signaling may improve efficacy of the therapy. Under conditions where oxidative stress is the initiating stimulus for apoptosis, it is assumed to simply trigger cell death as a result of cumulative oxidative damage. However, accumulating evidence now suggests that reactive oxygen species (ROS) may act as signaling molecules for the initiation and execution of the apoptotic death program in many, if not all, current models of apoptotic cell death [23, 24]. Signaling by ROS would not appear to be random, as previously assumed, but targeted at specific metabolic and signal transduction cellular components .
Here, we address the effects of a destructive/lethal PDT dose on the transcriptome by using transcriptional exon evidence oligo microarrays. This dose induces high levels of cytotoxicity and is expected to have significant impact on gene expression patterns. The expression alterations were observed by investigating both early responses, and responses post mobilization of major response pathways. We show that high levels of cellular cytotoxicity have a direct effect on cellular transcription levels and impair metabolic processes. Alternative splicing represents a key event in the control of gene expression [26–30]. Here, we tested to what extent mitochondrial damage caused by HAL-PDT modulates alternative splicing in a global manner.
Results and discussion
Rationale for selection of experimental parameters
5-Aminolevulinic acid (ALA), a precursor to porphyrins, is effective and widely used for PDT of a number of diseases [31–34]. However, a significant shortcoming of ALA is its limited ability to cross certain biological barriers (e.g. cellular membranes), probably due to its low lipid solubility. In contrast, ALA esters are more lipophilic and pass more easily through biological membranes than ALA itself. Hexaminolevulinate (HAL) is a hexyl ester of ALA with a higher lipophilicity. HAL has been shown to be 50–100 times more efficient than ALA at inducing cellular porphyrin formation with a high selectivity , and has been approved by the European Union for photodetection of bladder cancer. Thus, HAL is a promising compound for PDT therapy. On this basis, it is reasonable to assume that the mechanisms of action of ALA and HAL are comparable, and that gene expression profiles should be very similar. Therefore, only HAL was chosen for this study.
Studies are now in progress to test the use of PDT for several types of pre-cancerous conditions and cancer, including cancers of the skin, cervix, bladder, prostate, bile duct, pancreas, stomach, brain, head and neck, as well as lymphoma. PDT using topically applied ALA was first reported for the treatment of cutaneous T-cell lymphoma (CTCL) in 1994. Since then, there have been several reports of its usefulness in treating this disease [33, 36–39]. The role of PDT in CTCL to date has been in the treatment of individual patches, plaques, and tumors that have not responded to the other forms of skin directed therapy. While several PDT protocols have been evaluated, further studies remain in order to define the optimal use of PDT in treating patients with CTCL. Moreover, the use of PDT for ex vivo purging of autologous bone marrow graft has been proposed . High-dose chemotherapy supported by hematopoietic stem cells transplantation (HSCT) presents an effective way to cure lymphoma/leukemia. Although autologous HSCT has several advantages over allogenous HSCT, autografts may harbor residual occult malignant cells that can cause a tumor relapse after being reinfused to the patient. It is therefore desirable to remove the residual neoplastic cells from the autograft before being applied. The ability of malignant cells to selectively accumulate photosensitizers offers the possibility of using PDT in bone marrow purging. Recently, a study of the purging effects of PDT in leukemic cells mixed with normal bone marrow MNCs was published .
Here, we aimed to map general responses on gene expression after PDT therapy. Therefore we employed the Jurkat human T-cell leukemia cell line that previously has been used in multiple PDT-studies. The induction of apoptosis through translocation of apoptosis-inducing factor [42, 43] and caspase-3-like activation has been demonstrated for this cell line. Also, other sensitizers in PDT therapy have been shown to induce apoptosis in Jurkat cells [32, 44–46].
Dose and time course
The aim of this study was to determine the gene expression state of the cell in response to PDT immediately prior to and post switching to the programmed cell death. Here, we measured gene signatures that were likely to represent a combination of both protective and pro-apoptotic signals. The characterization of the transcriptome at early stages (1 h and 2 h) was chosen to reveal the state of the cell prerequisites to the execution of the cell death program.
It has been previously demonstrated that the appearance of cytoplasmic mRNA degradation products occur 4–8 h after induction of apoptosis, independent of the apoptotic signal and the cell line used . The purity and integrity of the RNA are critical for the overall success of RNA-based analysis, including gene expression profiling. For this reasons, the late (4 h) time point was selected to provide an insight into the later stages of this process, but still retain a sufficient numbers of viable cells and RNA integrity necessary for the technical execution of the analysis. In this study, the integrity of total RNA was measured by microcapillary electrophoresis and the degree of degradation was determined (data not shown). With the starting amount of cells kept equal across experiments, a time dependent decrease of the total amount of isolated total RNA was obtained. No compromise in the integrity of the RNA was observed. This indicates the effective removal of the dead cell fraction by the wash/centrifugation step, following degradation of leaked RNA.
Overview of transcriptome changes
A total of 170 probes (124 unique Entrez gene IDs) were altered at early (1 and 2 h) response (Fig. 2A). Of these 82.9% were up-regulated, i.e. 124 probes at 1 h and 61 probes at 2 h (Fig. 2B), while a total of 29 probes were identified as down-regulated at early response (Fig. 2C). Previously, we have reported on the stimulatory effects on the transcriptome using a related treatment modality, photochemical inhibition treatment (PCI) . PCI is based on photosensitizers with photochemical properties similar to those utilized in PDT. However, a weaker dose (LD 50%) is generally used, as the aim is not primarily to cause general cell toxicity. Interestingly, when the lethal PDT dose applied in the present study was compared to those induced by PCI, several of the early altered genes were identified as up-regulated with both modalities, indicating that both moderate (PCI) and high level (PDT) of oxidative stress are likely to invoke similar modulatory pathways, albeit with very different effects at later time points.
Histone related genes
Enriched KEGG pathways in the list of differentially expressed genes at 4 h after HAL-PDT
Total/Down regulated gene list
citrate cycle (TCA cycle)
ubiquitin mediated proteolysis
cholera – infection
phenylalanine, tyrosine and tryptophan biosynthesis
insulin signaling pathway
Up-regulated gene list
neuroactive ligand-receptor interaction
type i diabetes mellitus
fc epsilon ri signaling pathway
porphyrin and chlorophyll metabolism
hematopoietic cell lineage
Enriched GOTERM Cellular Component in the list of differentially expressed genes at 4 h after HAL-PDT
GOTERM Cellular Component (level 5)
Total/Down regulated gene list
mitochondrial inner membrane
large ribosomal subunit
cytosolic ribosome (sensu Eukaryota)
mitochondrial electron transport chain
cytosolic large ribosomal subunit (sensu Eukaryota)
heterogeneous nuclear ribonucleoprotein complex
small nucleolar ribonucleoprotein complex
endoplasmic reticulum lumen
proton-transporting ATP synthase complex (sensu Eukaryota)
small nuclear ribonucleoprotein complex
proton-transporting two-sector ATPase complex
organellar small ribosomal subunit
endoplasmic reticulum membrane
Up-regulated gene list
integral to plasma membrane
apical junction complex
microtubule associated complex
mitochondrial electron transport chain
The combination of the cellular responses (induction of histones and metallothioneins) in addition to induction of mitochondrial encoded genes may indicate a partial repair of mitochondrial and other cellular functions. However, it is in general difficult to assess the impact of the changes in gene expression at 4 h, as cell mortality is the endpoint. One of the reasons could be damaged translational machinery, given that ribosomal proteins were identified as direct targets (Tables 1, 2).
Other gene ontology processes found to be very significantly affected included those of the ribosome, cell cycle genes, proteosome, ubiquitin mediated proteolysis (Table 1), as well as protein transport, and ER to Golgi vesicle mediated transport (data not shown). This indicated that main cellular processes, such as the cell cycle and protein synthesis/transport were disrupted, leading to protein degradation through ubiquitine mediated proteolysis. In addition, the processes such pyrimidine and purine metabolism, glycolysis/gluconeogenesis, RNA/DNA metabolism, cellular protein metabolism, protein biosynthesis scored highly among enriched gene ontology groups indicating disruption of these processes. This seems to be an indication that the basic energy metabolism is shutting down, or at least is heavily affected, as one should expect from apoptotic cells.
Effect on alternative splicing
Counts of alternative splice variants
Number of alternative spliced genes, cut off fold change ≥1
Number of alternative spliced genes, cut off fold change ≥2
Number of alternative spliced genes, cut off fold change [1–1.99]
Upregulated alternative variants, cut off fold change ≥1
Upregulated alternative variants, cut off fold change ≥ 2
Upregulated alternative variants, cut off fold change [1–1.99]
Dowregulated alternative variants, cut off fold change ≥ 1
Dowregulated alternative variants, cut off fold change ≥ 2
Dowregulated alternative variants, cut off fold change [1–1.99]
Alternatives up and down for the same gene, cut off fold change ≥ 1
Alternatives up and down for the same gene, cut off fold change [1–1.99]
% of down regulated alternatives, cut off fold change ≥ 1
% of down regulated alternatives, cut off fold change ≥ 2
% of down regulated alternatives, cut off fold change [1–1.99]
Enriched GOTERM Biological Process in the list of alternatively spliced genes
Up-regulated splice variants, with fold change [≥1] at 4 h
regulation of protein metabolism
cellular protein metabolism
cytoskeleton organization and biogenesis
Down regulated splice variants, with fold change [≥1] at 4 h
cellular lipid metabolism
negative regulation of cellular metabolism
membrane lipid metabolism
regulation of progression through cell cycle
establishment of cellular localization
amino acid metabolism
intracellular protein transport
regulation of protein kinase activity
carboxylic acid metabolism
negative regulation of cell proliferation
regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism
cellular macromolecule catabolism
protein complex assembly
chromosome organization and biogenesis
Correspondence between alternative microarray platforms: cDNA and oligo microarrays
Ranking cDNA and Oligo microarray detected genes
Activating transcription factor 3
Metallothionein 1B (functional)
Histone 2, H2be
V-jun sarcoma virus 17 oncogene homolog (avian)
Jun D proto-oncogene
Immediate early response 2
Histone 1, H2ac
H3 histone, family 3B (H3.3B)
Histone 1, H1c
Guanine nucleotide binding protein (G protein), alpha z polypeptide
CCAAT/enhancer binding protein (C/EBP), beta
Splicing factor, arginine/serine-rich 3
Proline-rich nuclear receptor coactivator 1
phorbol-12-myristate-13-acetate-induced protein 1
Hypoanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)
Zinc finger protein 92 (HTF12)
Tumor necrosis factor, alpha-induced protein 3
Protein phosphatase, EF hand calcium-binding domain 1
Chromosome 9 open reading frame 27
In summary, the results provided new insights into how a PDT relevant dose alters gene expression. We confirmed known early defense response genes, and extended these to include the involvement also of other oxidative stress inducible gene groups, most notably the metallothioneins and histones. We also demonstrated that high levels of cellular cytotoxicity had direct effects on nuclear and mitochondrial DNA transcription levels in impairing metabolic processes. Furthermore, we attempted to identify how different signaling processes may be involved in the execution of cell death. The results indicated that mitochondrial damage caused by HAL-PDT modulates alternative splicing through unbalancing a vast number of isoform equilibriums, which may be an important contribution to the deadly outcome of HAL-PDT therapy.
Cell culture and PDT treatment
The human T-cell leukemia cell line, Jurkat, was maintained in RPMI 1640 medium containing 10% fetal calf serum (FCS), 100 U/ml penicillin, 100 μg/ml streptomycin and 1% glutamine in a fully humidified incubator (Nuaire US Autoflow) at 37°C with 5% CO2. In experiments with PDT, 8 × 105/ml of cells were seeded in 6-well plastic tissue-culture plates (Nunc) and incubated in the dark for 4 h in serum-free RPMI 1640 medium containing 5 μM of hexaminolevulinate (HAL) (PhotoCure ASA, Oslo, Norway).
Since the light penetration is undemanding for the cell line, the light source used in the present study has a broad spectrum with a range of 400–500 nm, fitting largely to the maximal absorption of porphyrins derived from ALA and its esters including HAL. Our previous studies have shown that the combination of HAL with the light source can kill various types of tumor cells efficiently [42, 43]. The cells were exposed to light from a bank of four fluorescent tubes (model 3026, Applied Photophysics, London, UK). The fluence rate of the light reaching the cells was 8 mW/cm2. The light doses of 80, 160 and 240 mJ/cm2 were used to determine the cell viability. The light dose of 160 mJ/cm2 was chosen to treat the cells used in microarray experiments. The cells were washed twice with medium immediately after illumination and incubated with fresh medium containing 10% FCS. Cells were washed twice with PBS before sampling.
Cell survival was measured by the MTS assay . After HAL-PDT, 100 μl of each sample was placed to 96-well plastic microplates (Nunc) and incubated at 37°C for 0, 1 and 3 h, followed by the addition of 20 μl of MTS (5 mg/ml) (Promega Corporation, Madisom, WI, USA) into each well for an additional 1 h-incubation. The absorbance at 490 nm was measured with a microplate reader (Labsystems Oy, Helsinki, Finland). The absorbance of blank wells containing medium and MTS, but no cells, was subtracted from all readings and cell survival was expressed as the fraction of control samples.
RNA purification and labelling
Total RNA was isolated using GenElute Mammalian Total RNA kit (Sigma, St. Louis, MO) according to the manufacturer's protocol. RNA concentrations were determined with NanoDrop spectrophotometer (NanoDrop Technologies). The integrity and degree of degradation of RNAs was calculated using Agilent 2100 Bioanalyzer (Agilent Technologies AS). Fluorescence-labelled cDNAs were synthesized from 20 μg of the total RNA using an indirect amino allyl microarray labelling kit (Faiplay, Stratagene, La Jolla, CA, USA) according to the manufacturer's recommendations.
Oligo microarrays and their hybridization
The oligo microarrays used in this study were obtained from The Norwegian Microarray Consortium, for details on the arrays, we refer to . The target oligos were the HEEBO (Human Exonic Evidence Based Oligonucleotide) set (Invitrogen). Probes included probes for constitutive, alternative exonic; alternative spliced/skipped exons, mitochondrial genes (mtDNA) for more details on oligos, we refer to . During analysis all probes were handled individually, also those that encoded the same gene. The microarray hybridization buffer (76 ul) contained each of the labeled probes, 16 μg poly A (Amersham Pharmacia Biotech AB), 8 μg yeast tRNA, 0.5 μg herring's sperm DNA, 5 × SSC, 0,1% SDS, 25% (v/v) formamid. Prior to hybridization, the solution was incubated for 2 min at 100°C and then centrifuged for 2 min at 13,000. The microarray slides were hybridised at 42°C overnight in a humid hybridization chamber (TeleChem International, Inc.). The slides were washed for twice in 0.5× SSC, 0.01% SDS, and 0.06× SSC for 5 min at room temperature. The slides were spun and dried immediately after washing.
The microarray experiment design was based on competitive hybridizations of HAL-PDT treated cells vs untreated. Total RNA was harvested from triplicate samples of treated and non-treated cells at 1, 2 and 4 h after HAL-PDT. Three replicated hybridization were performed for each time point.
cDNA microarays and their hybridization
The cDNA microarrays used in this study were obtained from The Norwegian Microarray Consortium, for details on the arrays, we refer to . The targets, approximately 15.000 unique I.M.A.G.E cDNA clones were from ResGen 40 k set. The hybridization volume of 110 μl consisted of: 8–10 μl of each of the labelled probes, 16 μg poly A (Amersham Biosciences), 15 μg human Cot-1 DNA (Invitrogen) and 85–90 μl of Microarray Hybridization Buffer #1 from Ambion (Austin, TX). The final mix was heated for 2 min at 100°C and after spinning down it was applied on a microarray. A hybridization station (Genomic Solutions, Inc., Ann Arbor, MI) was used for hybridization and wash, the details on hybridizations and wash can be found .
Data preparation and analysis
Slides were scanned using an Agilent Microarray scanner (Agilent Biotechnologies). The quantitative measurements of the fluorescence images were performed by the software GenePix 4000B (Axon Instruments, Union City, CA). The images (TIFF files) and extracted raw data (GRP files) were stored in a BASE 1.2.15 database . The spots that were technically flawed or flagged automatically by the GenePix software, spots with a diameter less than 60 μm were removed from the data of each microarray. The genes were preserved signal-to-noise ratio in one of the channel was equal or higher then 3 removing uncertain spots. Background-subtracted intensities less than one times the sdtev of the local background were assigned this value to avoid zero or negative values in the ratio calculations. Moreover, systematic errors were corrected by normalizing the data using a locally weighted scatter plot smoother, the method of pin-based lowess The genes were preserved if the values were experimentally obtained in more than 70% of the experimental matrix. The weighted K-nearest neighbours method was applied for imputation of missing values .
We used Limma package in R  to define differentially expressed genes. As we had three groups (1, 2 and 4 h) and three replicates in each group, the linear model fitting and empirical Bayes methods were used for assessing differential expression. The empirical Bayes approach is equivalent to shrinkage of the estimated sample variances towards a pooled estimate, resulting in far more stable inference when the number of arrays is small . To classify a series of related t-statistics as up, down or not significant, the multiple testing across genes and contrasts (1, 2 and 4 h groups) was used. To avoid the multiple testing problem  we have used Benjamine and Hochberg's method  to control the false discovery rate across the genes with restriction p < 0.05. The venn diagrams were prepared with Limma to visualize the intersections of the significant gene sets within groups. Hierarchical clustering of genes for visualisation of expression patterns was performed in MultiExperiment Viewer (MEV) . Functional classification was performed by using the Database for Annotation, Visualization and Integrated Discovery (DAVID, release 2.1) online tools. The relative enrichment of KEGG pathways (KEGG PATHWAY Database (July 19, 2006)) was calculated the number of genes, belonging to these functional categories in the list of significantly altered genes. The gene-enrichment of functional pathways measured by determining the number of genes, belonging to the pathway in the list of significantly altered genes weigh against to the total analysed/printed genes on arrays (background) using Fisher Exact test. For top raking of the genes, only 1 h post HAL-PDT experiments performed cDNA and oligo arrays were taken. The join was done using locus link IDs, so a gene appears as ranked only if locus links IDs present for both the cDNA and oligo significantly altered genes. Since many oligo probes map to the same locus link, the highest-ranking oligo probe for a particular locus link is used in the ranking.
Gel electrophoresis and immunoblotting
For protein isolation, the cell pellets were lysed on ice in 1 ml of lysis buffer (0.4% w/v SDS, 5 mM EDTA, 5 mM EGTA, 10 mM sodium pyrophosphate and 20 mM Tris-base; pH 7.2) for 30 min, briefly sonicated, diluted 1:2 in double strength SDS gel-loading buffer [double strength, 1% (w/v) SDS, 4.8 mM sodium deoxycholate, 10% (v/v) mercaptoethanol, 1% (v/v) Igepal CA-630, ~0.1% (w/v) Bromophenol Blue, 13,4% (v/v) glycerol and 120 mM Tris/HCl, pH 6.8] and boiled for 5 min at 95°C. After measuring the protein contents of the extracts with the BCA protein assay kit from Pierce (Rockford, USA) , 10 μg of samples were separated by SDS gel electrophoresis for 40 min at 200 V in 10% polyacrylamide gels containing 0.1% SDS. Molecular weight markers were included in all gels. Gel-separated proteins were transferred to nitrocellulose blotting membranes using a semi-dry transfer unit (Bio-Rad Laboratories, Hercules, CA, USA) with Towbin's blotting buffer (192 mM glycine, 20% methanol and 25 mM Tris-base; pH 8.3). The membranes were blocked by overnight incubation with 5% dry milk in TBS containing 0.2% Tween-20 (TBS-T) at 4°C, and washed three times for 10 min each in TBS-T. For detection of proteins, the membranes were incubated with the antibodies of MYC, ATF3 and JUN (diluted 1:1000 in TBS-T) overnight at 4°C, washed three times with TBS-T and incubated with the respective anti-rabbit or mouse-horseradish peroxidase-conjugated secondary antibodies (diluted 1:2000 in TBS-T) for 1 h at room temperature before being visualized by chemiluminescence using an ECL Western Detection Kit (Amersham Biosciences). To verify optimal blotting condition, the remaining proteins in the polyacrylamide gels were routinely stained with coomassie solution (0.1% (w/v) Coomassie blue R350, 20% (v/v) methanol, and 10% (v/v) acetic acid) for 2 hours and excess staining was removed by using a destaining solution (50% (v/v) methanol in water with 10% (v/v) acetic acid) over night.
Primers for RT-PCR
A program was written to create a concordance between locuslink IDs and HEEBO constitutive and alternative exon probes, using annotation information provided with the HEEBO probe set. This concordance grouped each locuslink ID with the oligo IDs of the probes targeting the exons contained within the locus.
For a each locus L, we applied a test to determine if there was a difference in expressed spliced isoforms between the treated and reference sample. At a hybridization at a given timepoint, we searched for at least one probe A derived from an alternatively expressed exon in L such that 1) The absolute value of log2ratio (A) was above a given threshold (fold change of PDT treated vs. none treated controls by 1 and 2) there existed a probe C in L from derived from a constitutive exon such that the absolute value of the difference between the log2ratios of A and C was equal to or greater than 1. Thus, for each hybridization, we found a (possibly empty) set of alternatively-expressed exon probes for each locus L. Since we performed three hybridizations are each timepoint, we required at least two of the three to agree in their results. Specifically, we required that there be a non-empty intersection between the set of alternatively-expressed exon probes from at least two experiments at the timepoint.
false discovery rate
reactive oxygen species
Kyoto Encyclopedia of Genes and Genomes.
The present work was supported by The Norwegian Cancer Society.
The microarrays were obtained through the Norwegian Microarray Consortium currently supported by the Functional Genomics Programme and the Research Council of Norway.
We also thank to Michael T.N. Møller for performing western blots, Ane Sager Longva for doing RT-PCRs and Timothy J. Lavelle for the critical reading of the manuscript.
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