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The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry. Results U glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. GABA addition to glioma cells increased proliferation rates. IDH mutation. Introduction Gliomas, glial cell derived central nervous system malignancies, are a heterogeneous, aggressive tumour type with poor prognosis.
The incidence of isocitrate dehydrogenase IDH mutations is high in low-grade gliomas. Despite the fact that these malignancies are still incurable, patients with IDH-mutant gliomas have a better prognosis and response to chemo-and radiotherapy than patients with IDH wild-type tumours [ 1 , 2 ].
IDH mutations can also be implicated in the formation of other tumour types acute myeloid leukaemia — AML, chondrosarcomas, intrahepatic cholangiocarcinoma — ICC. Based on highly detailed analyses of the genetic basis for malignant progression gene amplifications, mutations, loss of chromosome arms, gene expression, DNA methylation status , several altered pathways in IDH-mutated gliomas were characterised, including RTK-PI3K-mTOR, Notch signalling, cell cycle and DNA damage response regulation.
These studies concluded that IDH mutation is at the centre of epigenetic alterations in glioma cells [ 5 , 6 ]. In addition, the mutation has a negative impact on the function on the wild-type allele [ 9 ]. Moreover, mutated IDH1 not only causes 2-HG production, but also initiates changes in metabolic adaptation of mutated cells [ 12 ]. Because 2-HG and aKG are structurally very similar metabolites, 2-HG acts as a competitive inhibitor of aKG-dependent dioxygenases including prolyl-hydroxylases, histone- and DNA demethylases [ 13 , 14 , 15 ].
Cancer-related metabolic alterations, adaptations and their role in tumourigenesis and progression are extensively studied in many cancers. The metabolic characterisation of human gliomas started with the reinterpretation of Warburg effect suggesting that other substrates than glucose can also be oxidised by glioma cells [ 12 , 16 , 17 ], such as glutamine and acetate [ 18 , 19 , 20 ].
Previous results suggested that glioma cells adaptively run the TCA cycle backwards to power the electron transport chain, especially in case of IDH-mutant cells. Analogous to fumarate hydratase FH and succinate dehydrogenase SDH mutations, which can also cause oncometabolite production, IDH mutation provides an example of how a single mutation can reprogram cellular metabolism and affect pathobiology [ 13 , 15 , 24 ].
Recent years have yielded exciting findings in the field of tumour metabolism, and some aspects of these metabolic alterations related to IDH mutations have also been described [ 25 , 26 ]. Astrocytes and GABA-ergic and glutamatergic neurons play roles in the maintenance of the neurotransmitter pools of glutamate and gamma-aminobutyric acid GABA.
Astrocytes and neurons are in metabolic symbiosis, astrocytes can catabolise glutamate and GABA for supporting and regulating neuronal functions. An emerging question is whether glioma cells have the ability to use the GABA shunt to support energy production and proliferation. This indicates a need to understand the effect of produced 2-HG caused by IDH1 mutations on the former pathway. Our study provides an exciting opportunity to advance our knowledge of the effects of IDH1 mutation and 2-HG accumulation to identify several mechanisms which can help to understand the Janus-faced role of IDH1 mutations in the progression of gliomas — IDH mutations could be driver oncogenic alterations, however, IDH-mutant human gliomas have better prognosis than wild-type.
In the present study, the alterations of bioenergetic characteristics and different substrate oxidation capacities in relation to the expressions of relevant proteins in glioma cell lines were analysed Additional file 1 : Figure S1 summarises the analysed pathways. This may have special importance in survival, proliferation and metabolic adaptation of glioma cells. Methods All materials were purchased from Merck-Sigma-Aldrich Darmstadt, Germany , except where it is indicated in the text.
We selected concentrations based on previous publications. Cell proliferation measurements Beside cell counting the proliferation rate was analysed by sulforhodamine-B SRB assay which correlates to the protein content of the analysed samples. For h proliferation assays 2. The incubation period was 4 h, fluorescence was measured by Fluoroskan Ascent FL fluorimeter software Labsystems International.
Percentages of proliferation were given relative to control samples. Expression analysis of different proteins by Western blot Protein concentrations of cell extracts were measured with using Bradford assay Biorad. Assay to detect cellular respiration and extracellular pH changes Real-time measurements of oxygen consumption rate OCR , reflecting mitochondrial oxidation and extracellular acidification rate ECAR , indicated as a parameter of glycolytic activity, were performed on a Seahorse XF96 Analyzer Agilent Technologies, USA based on previous descriptions [ 30 , 31 , 32 ].
Following this, substrate utilisation was measured by using different substrates in parallel wells. During the measurements freshly prepared substrates glucose 10 mM, glutamine 2. Citrate, aKG, succinate, fumarate, malate, glutamate and 2-HG concentrations were assessed by using calibration curves obtained with the dilution of analytical purity standards in the range of 0.
Debrecen, Hungary. The mobile phase consisted of water containing 0. Quantitative analysis was performed in multiple reaction monitoring MRM mode. Three normal brain and renal tissues were included as controls. TMA sections were deparaffinised, endogenous peroxidase blocking was followed by antigen retrieval sodium citrate; pH 6. H-scores scale of 0— were determined by two independent pathologists with semi quantitative analysis of immunoreactivity using 3DHistech Pannoramic Viewer program according to Krencz et al.
The final H-score was calculated by averaging the H-scores of all the scores from the same tissue. Statistical analysis The data are presented as mean with standard deviation and calculated from three independent experiments with minimum three or more parallels depending on the method used. Results Characteristics of cellular respiration and glycolytic activity in glioma cells The basal oxygen consumption rates OCR among the investigated gliomas showed significant differences.
In contrast with the respiratory parameters, there were no differences in the basal extracellular acidification ECAR rates. However, glucose addition reveals alteration in the metabolic adaptation of gliomas. Lactate productions using glucose administration with or without mitochondrial respiratory inhibitor were the highest in U87 MG cells, which have the lowest basal respiratory activity Fig. These findings indicate an inverse relationship between the basal oxygen consumption and the glycolytic activity.
Additionally, we compared the glutamine metabolising properties of the examined gliomas. Using same cell density, time-dependent growth showed individual differences in these glioma cells Fig. U MG cells have the fastest proliferation and these cells have both high glucose utilisation and high respiratory capacity. Cell proliferation was monitored by SRB test using 2. Of course, we did not say anything. The policeman then spoke of hostile, agitating Westerners and of political news items interrupting the music programmes on Radio Free Europe.
A classmate of mine stood up and said no, the news came on every full hour, with the music starting ten minutes later Be careful, said my father, and do not fall into the trap of such provocateurs. They were immediately taken away. On the 25th anniversary of the Revolution of , the city was simply swarming with detectives.
They even attempted to rope the boy in by having him sign some documents—it was the Youth Protection Agency, the one that was supposed to protect the youth from itself. They went after my classmate quite aggressively, as well. Once we graduated from secondary school, our headmistress admitted to us that she had to beg the Agency to leave her alone, as she had thoughts of suicide.
She had tried it before, finished school in , but did commit suicide later. Did he talk to you about that? As teenagers, my brother and I used to take it with irony when he told us about being followed or even pointed people out in the street. We said it must have been some sort of delusion of grandeur or paranoia. After , we, of course, found out that he was absolutely right. Actually, he even understated the situation. He told us a lot of stories about , but, as a teenager, I used to doubt them.
I thought he injected too much importance into his own role in the revolution. I still feel the same way. My father was a young teacher at that time, which is how they regarded him. In politics, creating your own legend and mythology is also quite important. My grandfather often tried to calm my father down and talk him out of being so radical.
He once told my father that, as a Government Commissioner, he had been absolutely sure about the Gestapo spying on him through somebody. It turned out to be his secretary, so my grandfather always made sure to leave something on his desk he could report about. In fact, my father was very cautious about this matter. We were living a modest life and he only started earning more in the mids, when he became deputy director at the Museum.
We owe a lot to Emil Schultheisz,8 a friend who was minister of health back then. Had we given in to provocation, he would have had to suffer the retribution. He did not want to become easy to manipulate, and he did not want anybody to get him through his children. He explained all this to us when I was years old. When we later travelled to the West, we read the works of Hungarian writers in emigration, but we did not try to smuggle them back to Hungary because of this.
We could get them at home. My father did not keep contact with the so-called democratic opposition,12 with Demszky13 and his peers. He asked us not to frequent such circles either. My father said if we were interested in anything, Orwell or others, even Hungarians, he could get them all via his contacts. An antiquities trader visited my father in the museum quite often, and he used to buy something from this man sometimes just to help him, but, at the same time, he suspected that the man was a spy.
My father was in a rather rotten mood during the s. He feared he was running out of time and that he would never have the opportunity to be an active politician. He was in his sixties. He was always saying that working at the museum was only his hobby. From morning to dusk, he was all about politics. During these years, he occupied himself by determining who he would have chosen for his government in the place of the German chancellor. A couple of years later, he actually met Kohl,17 and they discussed German politics.
Do you remember an event or a moment when you felt day X was approaching? As to how long this crumbling phase or morass would last, nobody had any idea. My father cautiously started to dip his toe into politics. The museum served as a meeting place, many foreigners visited him, as well, and he was discovered by the embassies. He received a lot of invitations. He worked less and less at the museum. In other words, he thought the communist experiment would fail due to demographic reasons.
At school, you obviously did not receive a Christian or national education. What did you pick up from home? But, later, he did encourage me to go over there to take photos, and he was glad I went quite often. Our family was rather on the patriotic than on the Christian side in a religious sense. My grandfather went to church and so did my mother in most of the cases, as well. My older brother had been an altar boy, but I had not. My father did not force it, he asked me if I wanted to go.
I said no, and he accepted it. Getting to know the world of the Bible would have been interesting and useful, too, but I rather spent my Sunday mornings playing football. That was how I felt at that age. I have never really fitted into my family well, my critics always said I was a vagabond. Whatever that may mean, there was some truth in it. I could not complete the grammar test as quickly as I should have. This kind of dysgraphia had been with me throughout my school years, although, most of the time, it was only considered naughtiness.
Later, I became a photojournalist. Was it exactly this difference that attracted you to it? It falls quite far from the world of lawyers, that is true. The prospect of being a photojournalist just came along naturally. I was going over to Transylvania a lot to take pictures.
Without any formal training, I became a photojournalist then and there. I have never had any regrets about this. By the time the general atmosphere of the regime change hit in , I was already a photographer. Wherever there was something happening in those years, I was there.
During the restructuring period of the social system, both you and your father found yourselves in the thick of politics. Photojournalists are always in a strange situation as they are never fully inside but never fully outside either. Everyone knows you are a good photographer, you know, too, that it is not about that.
They were looking for a young photographer who did not mind working hard all day. I was 24, so I said I would be happy to do that. Those days were quite pleasant for the press and especially for the photographers. Today we might say they were having a good life.
The press was very progressive and respected around the time of the regime change. The media thought it was actually dictating the regime change when, in reality, it was only one of the major players. The true extent of the economic and political crisis of the communist bloc was seen most clearly by the KGB.
At certain times, one of them was more powerful than the other two. It is no wonder that only the KGB survived the dissolution of the Soviet Union in an institutional sense, although not in its full glory. As an empire, it had and still has access to worldwide, global intelligence.
During my MTI days, I once went to the Jurta Theatre28 and took a bunch of photos at the event, which were never got published. They obviously knew who I was. He also had a good eye for news items. They did not know my father at all until the round table talks, then they realised who I was. In the autumn, I decided to leave on my own accord before the unfair photo editor could sack me.
I got hired by Ferenc L. It was clear neither of us wanted to work with the other. You were a successful photographer bringing home well-received portfolios from your international assignments, as well. Taking photos at the Opposition Round Table was a weird feeling for me: I saw my father sitting there at the table, then, later, the same evening, he was sitting at home by the kitchen table.
I think by that time he felt I had found my calling. When I came home, I told him about the exhibition I was about to have in the Buda Castle, hoping he would come to the opening. If I am there, people will focus on me instead of you. Eventually, he did see my exhibition with great interest. I was 29 at that time, and my father did not want to steal the show from me.
His book series was basically my bible. During his illness, he could no longer sleep without sleeping pills. Apparently, he used to take some of my Transylvanian photos to cabinet meetings sometimes to show them to people, which I only found out about after his death. He never mentioned it to me. They were not very successful in creating their own media outlets either. My father liked to overmysticise his early writings.
There is no way you could win them over with anything. They listened to his explications with open mouths then they smeared him big time in their articles. Maybe his experiences made your father distrustful. This is true, and a catchy way of putting it. Has my father written all over it. However, the media war32 is raging on to this day and the adversaries are irreconcilable. The magazines I worked for started to disappear. I thought it was time to study.
With a scholarship I went to America, after that I started a media and then a political science major at the university. How different everything was back then compared to our present days! I told the minister that I needed a laptop, but they were only giving those automatically to deputy undersecretaries and above.
I thanked her but could not accept; imagine how everybody would have hated me on the corridor if they found out! Later, I bought one for myself. In those days, there were news about you having political ambitions, as well. Back in , Ibolya asked me whether I was truly interested in becoming a member of parliament.
I told her I had studied the subject, that I was interested in it, and that I would have been the fourth generation of my family in the Hungarian Parliament. By January, her offer did not stand any more. Not because of me personally, but because you cannot afford to play like an amateur with a name like Antall. Later, when Lajos Bokros36 came more and more to the spotlight, I no longer wanted anything to do with those people.
Once they even considered me for the party board. But where are they now? They succeeded in relegating MDF to the history books In your opinion, what led to the breakup of the MDF? They howled me down, then they got 1. My father was of the opinion that the already existing infrastructure should always be utilised, and it should not be let go for any reason. In my opinion, he would have made a serious mistake on his own in six months or a year.
What I really blame the MDF for is how they neglected the international relationships that my father had secured. Sadly, she did not follow up on these. The MDF did not have a single national paper, television, or radio. You cannot really make it like that They simply realised that nobody could last very long in politics without decent party infrastructure.
With this, he basically achieved what my father had been aiming for in I would like to ask about a couple of names directly. He was a political opponent, but my father never confronted him. He was the brains behind most anti-Antall rebellions.
Naturally, it was pretty rough for my father to deal with internal attacks while trying to save the country from a crisis. On the other hand, it is a natural part of politics to have rivals within a party. He was looking for a pragmatic person for that job. Since it was a very sensitive task, he wanted to give it to a suitable, trustworthy person.
Was he similar to a person you have just described? I never saw him again. Is your father at home? That was the place he retired from. He was a stranger to party politics, he did not know the MDF, and he evaluated people incorrectly. He was rather annoyed by party politics.
Even on the party board he advised self-moderation to other members with a more nervous nature. Yes, he is married to my older cousin. I respect him for a lot of things including his commitment to Atlantic relations and his professional knowledge. He had to put up with a lot of unworthy attacks as Foreign Minister,44 and he took a lot of hits for Antall. I cannot really comprehend his current work. Sometimes, I still get angry over politics and rant about the general ignorance of politicians.
In fact, I consider myself more an analyst than a front line person, and the mentioned information vortex comes in handy in leading the Knowledge Centre. Reagan realised that the Soviet Union was no longer able to keep up with the arms race America had forced it into. Gorbachev was not a great politician in my opinion, in many respects reminiscent of Imre Pozsgay47 always taking a step with the worst timing , but, at least, he did not hinder the process.
It is interesting that, in Russia, he is disliked to this day and is considered a traitor for breaking up the Soviet Union. My father had a strong bond to the nation, and he thought it important to orient Hungary towards the West. I think the West acted pretty lazily on this last point and, ultimately, failed to keep Ukraine on its feet. They lacked the political and economic will to do it.
The Americans felt too comfortable about winning the Cold War, and so they reacted late. A note on the USA: what they win in the theatre of war, they lose on the political ground. It was the same with Vietnam, too.
You have met a lot of politicians. Who had the biggest effect on you? John Paul II will always remain the Pope to me. I had the pleasure of meeting the Holy Father on multiple occasions. The time we met him in his personal study in probably had the most profound effect on me.
We were escorted through immense halls by an entourage, the Swiss Guard were standing at the door. We had to wait outside a small room. His body was broken, but his spirit was still going strong. The political and social transition in Hungary has been called many things throughout the years.
It was a negotiated revolution with revolutionary changes taking place at a desk peacefully, preventing a very real revolution.
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