Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways
- Siraj M. El Jamal1,
- Erin B. Taylor2,
- Zakaria Y. Abd Elmageed3,
- Abdulhadi A. Alamodi2,
- Denis Selimovic4, 5,
- Abdulaziz Alkhateeb6, 7,
- Matthias Hannig4,
- Sofie Y. Hassan6,
- Simeon Santourlidis8,
- Paul L. Friedlander3,
- Youssef Haikel9, 10,
- Srinivasan Vijaykumar11, 12,
- Emad Kandil3 and
- Mohamed Hassan1, 4, 9, 12Email author
© The Author(s) 2016
Received: 25 November 2015
Accepted: 15 June 2016
Published: 2 August 2016
Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail.
IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress.
In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.
KeywordsHNSCC IDO HO-1 FN-γ JAK STAT1
The tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells . Interferon gamma (IFNγ) is one of the central cytokines that coordinates tumor immune responses and the associated biological consequences . IFN-γ is a pleiotropic cytokine with multiple biological functions including immune cell activation [3, 4] and induction of the major histocompatibility complex (MHC) molecules both in normal and neoplastic cells [5, 6]. Besides its ability to trigger cell cycle arrest and apoptosis [7–10], IFN-γ shows anti-tumor activity in patients with advanced head and neck squamous cell carcinoma (HNSCC)  or non-small-cell lung carcinoma (NSCLC) . Although there is clinical data highlighting the reliability of IFN-γ as an anti-tumor agent , the molecular action of IFN-γ as anti-cancer agent has not been fully investigated. Because the current reported studies on the molecular action of IFN-γ in tumor cells are merely speculative, the aim of the present study is to elucidate, in detail, the mechanisms which are responsible for the modulation of IFN-γ-induced effects on HNSCC cells.
IFNγ coordinates cellular functions via transcriptional regulation of innate and adaptive immune response-associated genes such as indoleamine 2,3-dioxygenase (IDO) . IDO is a rate limiting enzyme in the kynurenine enzymatic pathway that converts tryptophan (Trp) to N-formyl-kynurenine, which is the main source for the production of the cellular cofactor NAD+ . While IDO has been found to be constitutively expressed in a limited number of human tissues , its induction and activation are tissue-specific and agent-dependent [15–17]. The induction of IDO by lipopolysaccharides (LPS), IFNγ, tumor necrosis factor alpha (TNF-α) and Fas receptor agonist (CH11) has been reported in different cell types [15, 18–20]. An in vivo induction of IDO is associated with IFNγ-mediated inflammation that mediates the innate immune response to intracellular pathogens and bacterial infection [21–24]. IDO is expressed in a wide array of human cancers , and the contribution of IDO in the regulation of tumor cell death has been demonstrated in several studies [18, 19, 26, 27]. In accordance, it is expected that IDO contributes to the regulation of IFNγ-induced cell death.
Herein we demonstrate an essential role for IDO as an apoptotic mediator during the course of IFNγ-induced death of HNSCC cells via a mechanism mediated by IDO-dependent suppression of HO-1.
Assessment of cell survival
Human head and neck squamous cell carcinoma (HNSCC), CLS-354 CLS (Cell Lines Service GmbH, Germany) and SCC nasal septum, RPMI 2650 (ATCC® CCL-30™) obtained from the American Tissue Culture Collection (ATCC, Manassas, VA, USA) were seeded in 96-microwell plates (1 × 104 cells/well), (Nunc, Waltham, MA, USA). The cells were challenged with IFNγ (1000 U/ml) for the indicated time periods. The percentage of viable cells was then determined using the colorimetric MTT assay (Roche, Bâle, Switzerland) as described .
The knockdown of IDO gene was performed using siRNA, and negative control siRNA as described in the manufacturer’s protocol (Qiagen, Hilden; Germany). The transfection of the cell lines was performed using lipofectamine 2000 (Invetrogen) as described .
Assay for intracellular IDO activity
The CLS-354 and RPMI 2650 cell lines (1 × 104) were allowed to grow overnight in a 24-well plate. The cells were treated with IFNγ (1000 U/ml) for 48 h. The treated and control cells were harvested and washed three times in phosphate buffered saline (PBS). The cell pellet was snap frozen at −70 °C and next day was homogenized in 0.5 ml PBS. Centrifugation was performed at 15,000×g for 10 min at 4 °C, then the supernatant was carefully collected for measuring IDO activity as previously described . Briefly, the cell extract was mixed with 100 μl reaction buffer (100 mM potassium phosphate buffer pH 6.5, 40 mM ascorbate, 20 μM methylene blue, 200 μg/ml catalase, 800 μM l-tryptophan). This step followed by incubation at 37 °C to activate the IDO enzyme to convert l-tryptophan to N-formyl-kynurenine. About 30 min later, the termination of the reaction was performed following the addition of 49 μl of trichloracetic acid (30 %). Following hydrolysis process of N-formyl-kynurenine to kynurenine has been completed, Then the measurement of the enzyme activity was performed by mixing of 100 μl of reaction mixture together with 100 μl Ehrlich reagent (0.4 % p-methyaminobenzaldehyde/acetic acid) using a Microplate reader (ImmunoReader NJ-2000 Nunc, Wiesbaden, Germany). The absorbance was at 490 nm.
Protein analysis was performed using standard immune blotting. The following antibodies were used at the indicated dilution: anti-Noxa (SC-2697) 1:1000; anti-cytochrome (#4212), 1:1000; anti-caspase 3 (#7190), 1:1000; anti-caspase 9 (#9501), 1:1000; anti-PARP (#9542), 1:500 (each Cell Signaling Technology Inc., Danvers, MA, USA); anti-IDO antibody 1:500 (BioGenes, Berlin, Germany); anti-ASK1 (Sc-7931), 1:500; anti-p-ASK1 (Sc-109911), 1:1000; anti-JNK (Sc-474), 1:1000; anti-p-JNK (SC-6254), 1:1000; anti-p38 (Sc-535), 1:1000; anti-p-p38 (Sc-7973), 1:1000; anti-Actin (Sc-1615), 1:5.000; anti-Tom20 (Sc-11415), 1:100; anti-Bap31 (Sc-18579), 1:1000; anti-HO-1 (sc-10789), 1:1000; anti-p-JAK1 (sc-16773), 1:1000, anti-IRE1α (Sc-20790), 1:500; anti-PERK (SC-9477), 1:1000; (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA); anti-IκBα (Sc-7182), 1:1000; anti-p-IκBα (AF4809, R&D system), 1:1000; anti-JAK1 antibody (ab47435), 1:1000; anti-IRF1 antibody (ab55330), 1:1000 (each ABCAM).
Extraction of nuclear proteins
The extraction of the nuclear proteins from IFNγ-treated CLS-354 and RPMI 2650, and control cells was performed as described previously . Briefly, following the washing twice with ice-cold PBS buffer the cells were harvested from culture dish with 500 μl of buffer A (20 mM Hepes, pH 7.9; 10 mM NaCl, 0.2 mM EDTA; and 2 mM DTT) supplemented with a recommended concentration of protease inhibitors. After the incubation on ice for 10 min the cells were centrifuged at 14,000×g for 3 min to sediment the cell nuclei. The supernatant the contains the cytoplasmic protein was kept at −20 °C for further analysis, while the nuclear pellet was used to extract the nuclear proteins. Accordingly the collected nuclear pellet was resuspended in 50 µl of buffer C (20 mM Hepes, pH 7.9; 420 mM NaCl, 0.2 mM EDTA; 2 mM DTT; 1 mM Na3VO4, 25 % glycerol) with appropriate amount of protease inhibitors. After the incubation on ice for 20 min the nuclear proteins were purified by the at 14,000×g for 3 min. The supernatant that contains the nuclear protein was collected for direct analysis or stored at −80 °C until use.
Electrophoretic mobility shift assay
The DNA-binding activity of the transcription factors have been analysed as described previously . Briefly, the double stranded synthetic oligonucleotides that represent the specific binding sites of the corresponding transcription factors including, AP-1, ATF-2, p53, NF-κB, STAT1, IRF-1 each purchased from Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA. The double stranded DNA consensus sequence consensus were end-labelled with [γ-32P] ATP (Hartmann Analytika, Munich, Germany) using T4 polynucleotide kinase (Genecraft, Lüdinghausen, Germany). While the measurement of the DNA-binding activity of each transcription factors was performed by the incubation of 4 µg of nuclear extracts with a labelled probe of the transcription factors of interest in a total reaction volume of 30 µl containing EMSA binding buffer (10 mM Tris, pH 7.5; 50 mM NaCl, 1 mM EDTA; 1 mM MgCl2; 0.5 mM DTT and 4 % glycerol). After the incubation for 30 min at room temperature the DNA-binding activity of the transcription factors were analyzed by electrophoresis for 3 h at 100 V in 0.5× Tris–borate-EDTA running buffer at room temperature. The dried gel was visualized by exposure to high performance autoradiography film.
Flow cytometry analysis of apoptosis using annexin V/PI
The analysis of apoptosis of IFNγ-treated and control cells was performed following the staining with 5 µl of annexin V-FITC (Vybrant; Invitrogen, Karlsruhe, Germany) and 5 µl propodeum iodide (100 µg/ml). After the incubation for 15 min at room temperature the number of apoptotic cells were assessed by flow cytometry described previously .
Measurement of mitochondrial membrane potential (ΔΨm) using JC-1
IFNγ- treated CLS-354 and RPMI 2650 cells were stained with 10 μM JC-1 (10 mM; Biotrend, Cologne, Germany) for 30 min at room temperature in the dark. The intensities of green (520–530 nm) and red fluorescence (>550 nm) of 50,000 individual cells were analyzed by flow cytometry as described previously .
Measurement of reactive of oxygen species
The measurement of reactive oxygen species (ROS) in IFNγ- treated and control cells was performed by flow cytometry following the staining with DHR 123 (Sigma) as described .
IFNγ- treated and control cells were subjected to immunofluorescence staining as described . Primary antibodies, anti-Noxa (SC-2697), 1:200; anti-Tom20 (Sc-11415), 1:200; anti-Bap31 (Sc-18579), 1:200 (each Santa Cruz Biotechnology Inc., CA, USA) were incubated treated and control cells for 2 h at room temperature. After three successive washing with PBS, the cells were incubated with Alexa Flour labelled secondary antibodies for 2 h at room temperature protected from light. To remove nonspecific binding of the secondary antibodies, the cells were washed three times with PBS, and subsequently mounted using DAKO mounting medium. Photomicrographs were taken on a fluorescence microscope (Leica, Wetzlar, Germany).
Preparation of mitochondrial and endoplasmic reticulum fractions
The preparation of mitochondrial and endoplasmic reticulum (ER) fractions was performed as described previously . Briefly, IFNγ- treated and control cells (CLS-354 and RPMI 2650) were scraped off with 5 ml of phosphate-buffered saline and collected by the centrifugation at 600×g for 5 min. After three washing in PBS buffer the cells have been washed, resuspended and homogenized in PBS buffer. After the centrifugation at 600×g for 5 min, the cell the supernatant was layered over a discontinuous gradient of 40 and 60 % sucrose in HE buffer (3 and 1 ml, respectively). Following the centrifugation at 100,000×g for 3 h, aliquots of the corresponding of the mitochondrial or ER fractions were precipitated with 10 % trichloroacetic acid (TCA) were directly subjected to western blot analysis or stored at −80 °C until use.
The statistical analysis was performed by considering the average of a at least three independent experiments (n = 3) and average values are expressed as the mean ± SD. The data analysis was performed using Student’s t test method.
Effect of IFNγ on the viability of HNSCC cells
IFNγ-induced expression of IDO is associated with the suppression of heme oxygenase-1
The exposure of HNSCC cells to IFNγ is associated with the activation of ASK1-dependent pathways
IFNγ-induced accumulation of ROS is attributed to the suppression of HO-1 by IDO
The pre-treatment of HNSCC cells with NAC blocks IFNγ-induced activation of ASK1-JNK, ASK-p38 and NF-κB pathways
IFNγ-induced apoptosis of HNSCC cells is the consequence of Noxa-mediated mitochondrial dysregulation
The present study provides a new insight into the mechanistic role of IFNγ-induced apoptosis of HNSCC cells and describes the possible role of IDO in the modulation of IFNγ-induced apoptosis during the course of immune therapy. The treatment of the HNSCC with IFNγ at a concentration of 1000 IU/ml is based on the determined IC50 as well as on the recommended dose by Yonekura et al. as described . IFNγ-induced apoptosis of HNSCC cells is a result of the IDO-induced suppression of HO-1, which leads to the increased accumulation of ROS that, in turn, triggers the induction of oxidative stress-associated pathways. These pathways include ASK1-JNK, ASK-p38 and ASK1-IKK/NF-κB that are essential for the induction of the pro-apoptotic protein Noxa. The subcellular localization of Noxa protein triggers mitochondrial dysregulation, an essential step for the initiation of apoptosis. Accordingly, the present study demonstrated the involvement of ASK1-JNK-p53/AP-1 and ASK1-IKK-NF-κB pathways in the modulation of IFNγ-induced Noxa expression. The activation of these signalling pathways is expected to be the consequence of IDO-induced suppression of HO-1 leading to ROS. Although the subcellular localization of Noxa protein to both ER and mitochondria has been observed, Noxa-induced mitochondrial damage seems to be essential for IFNγ-induced apoptosis of HNSCC cells. The localization of Noxa protein to mitochondria is associated with the loss of ΔΨm and the subsequent release of cytochrome c, and, cleavage of caspases-9, 3 and PARP, whereas IFNγ-induced Noxa to ER seems to be associated with the induction of ER stress, as evidenced by the phosphorylation of PERK and IRE1α.
IFNγ exerts its pleiotropic effects on normal and malignant cells via the interaction with a specific receptor that is commonly expressed on the surface of most eukaryotic cells [37–39]. The role of IFNγ in the regulation of IDO has been reported in several studies [40, 41]. IFNγ- induced IDO is mediated by JAK-STAT pathway-dependent mechanism(s) . IDO belongs to a pattern of gene transcripts such as JAK2, IRF-1 and STAT1α . Thus, the activation of the JAK-STAT pathway is associated mainly with the increased phosphorylation of JAK1 and the induction of both expression and DNA-binding activity of IRF-1.
The rescue of IFNγ-induced apoptosis by IDO inhibition provides evidence for the involvement of IDO in the modulation of IFNγ-induced apoptosis. Although the role of IDO as apoptotic mediator has been described previously [18, 43], we describe for the first time a central role for IDO in the modulation of IFNγ-induced apoptosis of HNSCC cells. Apoptosis of HNSCC cells by IFNγ is regulated by IDO-mediated suppression of HO-1 leading to the accumulation of ROS. As a consequence, the accumulation of ROS triggers the activation of ASK1-JNK and ASK1-NF-κB pathways [18, 33]. The role of HO-1 in the inhibition of apoptosis via mechanism mediated by the suppression of oxidative stress-associated pathways has been reported in several studies [44–46]. In accordance, we found that the induction of IDO expression or activation results in the suppression of HO-1 protein that, in turn leads to ROS accumulation. The involvement of IDO in the modulation of IFNγ-induced apoptosis is supported by the findings that demonstrate the rescue of IFNγ-induced suppression of HO-1 along with the inhibition of IFNγ-induced apoptosis in response to the knockdown of IDO expression or inhibition of IDO activity.
The role of mitochondrial dysregulation associated pathways in the modulation of IFNγ-induced apoptosis has been reported in several studies [47–49]. Similarly, we found that IFNγ-induced mitochondrial damage is the consequence of the activation of ASK1-JNK, ASK1-JNK and NF-κB pathways leading to the activation of the transcription factors AP-1, p53 and NF-κB. These transcription factors are thought to form a transcription complex that is essential for the promoter activation of Noxa gene. Since the induction of apoptosis of HNSCC cells by IFNγ is associated with Noxa-induced loss of Δψm.
activating transcription factor 2
activator protein 1
apoptosis signal-regulating kinase
electrophoretic mobility shift assay
head and neck squamous cell carcinoma
protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring-1α
interferon regulatory factor 1
major histocompatibility complex
nuclear factor kappa-light-chain-enhancer of activated B cells
poly ADP ribose polymerase
protein kinase RNA-like endoplasmic reticulum kinase
reactive oxygen species
signal transducer and activator of transcription
mitochondrial membrane potential
SME and EBT carried out the Flow cytometry; ZYA, SYH and AAA carried out immune fluorescence, DS and MH conceived the study design and designed the experiments AA, MH and SYH carried out the immunoblotting; DS and MH carried out EMSA; SS and PLF carried out MMT assay; YH, SV, EK and MH prepared the manuscript; All authors read and approved the manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
Authors are encouraged to make readily reproducible materials described in this manuscript freely available to any use them, without breaching participant confidentiality.
This work was supported by grants from German Research Foundation (HA 5081/3-1), from L’Alsace contre le cancer, France, German cancer research foundation (10-2202-Ha1) to M. Hassan.
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