Tratto da "Salute 24" (vedi articolo originale)
Leggi articolo originale su European Heart Journal
Niente di meglio di un quotidiano e vigoroso esercizio fisico per favorire la riabilitazione dopo un attacco di cuore: secondo uno studio pubblicato sull'European Heart Journal dai ricercatori della Liverpool John Moores University (Regno Unito), il movimento fisico non blando aiuterebbe le cellule staminali cardiache «dormienti» ad attivarsi, stimolando la crescita di nuovo tessuto cardiaco e favorendo, quindi, il recupero post-insufficienza cardiaca.
Lo studio, per ora condotto su un gruppo di topi, ha dimostrato che lo sport - mezz'ora di tapis roulant 4 volte a settimana, per 4 settimane - rende attive più del 60% delle cellule staminali cardiache che solitamente, negli adulti, rimangono dormienti, oltre a migliorare la capacità aerobica e l'irrorazione sanguigna.
Dopo solo due settimane di esercizio aerobico i topi avevano infatti aumentato il numero di cardiomiociti - le cellule battenti del tessuto cardiaco - del 7%.
Questo studio è il primo del suo genere a suggerire che la riabilitazione basata sul movimento fisico potrebbe avere lo stesso effetto sulle cellule dormienti delle iniezioni di apposite sostanze chimiche che stimolino le staminali stesse a produrre nuovo tessuto, e aggiunge nuove evidenze scientifiche che confermano che il cuore può essere in grado di rigenerarsi autonomamente.
Altri studi dovranno però essere condotti per comprendere se gli stessi effetti possono essere sortiti sugli uomini.
sabato 29 dicembre 2012
Un ormone “stonato” alimenta il tumore
Tratto da "Salute 24" (vedi articolo originale)
Tumori e metastasi, colpa di una danza stonata.
Quella di un meccanismo utile allo sviluppo embrionale, che per un “cortocircuito” va in tilt e accende il gene della staminalità tumorale.
Grazie a gruppo di ricercatori dell’Università degli Studi di Padova, guidati da Stefano Piccolo – Piccolo ha appena ricevuto il premio scientifico FIRC “Guido Venosta” - è più chiaro il rapporto tra l'eccesso dell’ormone Wnt, normalmente coinvolto nella costruzione degli organi e nei processi rigenerativi, e il gene TAZ che “invia” staminali a supporto del tumore. Lo studio è pubblicato su Cell.
In condizioni normali lo sviluppo di un nuovo organo avviene solo durante lo sviluppo embrionale, e solo pochi organi, come il fegato, sono capaci di rigenerarsi dopo aver subito un danno.
Il cancro è un "organo" che ha scoperto il segreto di come riprodurre se stesso, ed è grazie alle sue cellule staminali che si possono sviluppare le metastasi, con ricadute dopo la chemioterapia.
Le cellule tumorali da sole però non riuscirebbero a fare molto e anche il più aggressivo dei tumori ha bisogno di ricevere parecchi segnali dall’ambiente che lo circonda.
Uno di questi segnali viene da un ormone che si chiama Wnt: un fattore attivo durante lo sviluppo embrionale e nei normali processi rigenerativi.
Lo studio di Stefano Piccolo, che porta la firma di Luca Azzolin e Michelangelo Cordenonsi, spiega come l'eccesso di Wnt attivi nella cellula un gene maestro della staminalità tumorale, chiamato TAZ.
TAZ era già noto ai ricercatori: è un gene che durante lo sviluppo di un organo controlla le sue dimensioni e animali che per difetti genetici nascono con troppo TAZ sviluppano organi giganteschi.
Lo stesso meccanismo viziato che può portare al processo di crescita di un tumore e la proliferazione delle metastasi, versione stonata di quella danza armoniosa che guida invece lo sviluppo embrionale.
La scoperta apre nuove prospettive terapeutiche: in futuro, grazie a farmaci mirati e anticorpi monoclonali sarà possibile colpire con un unico vettore sia Wnt che TAZ e arrestare, quindi, lo sviluppo della malattia.
Tumori e metastasi, colpa di una danza stonata.
Quella di un meccanismo utile allo sviluppo embrionale, che per un “cortocircuito” va in tilt e accende il gene della staminalità tumorale.
Grazie a gruppo di ricercatori dell’Università degli Studi di Padova, guidati da Stefano Piccolo – Piccolo ha appena ricevuto il premio scientifico FIRC “Guido Venosta” - è più chiaro il rapporto tra l'eccesso dell’ormone Wnt, normalmente coinvolto nella costruzione degli organi e nei processi rigenerativi, e il gene TAZ che “invia” staminali a supporto del tumore. Lo studio è pubblicato su Cell.
In condizioni normali lo sviluppo di un nuovo organo avviene solo durante lo sviluppo embrionale, e solo pochi organi, come il fegato, sono capaci di rigenerarsi dopo aver subito un danno.
Il cancro è un "organo" che ha scoperto il segreto di come riprodurre se stesso, ed è grazie alle sue cellule staminali che si possono sviluppare le metastasi, con ricadute dopo la chemioterapia.
Le cellule tumorali da sole però non riuscirebbero a fare molto e anche il più aggressivo dei tumori ha bisogno di ricevere parecchi segnali dall’ambiente che lo circonda.
Uno di questi segnali viene da un ormone che si chiama Wnt: un fattore attivo durante lo sviluppo embrionale e nei normali processi rigenerativi.
Lo studio di Stefano Piccolo, che porta la firma di Luca Azzolin e Michelangelo Cordenonsi, spiega come l'eccesso di Wnt attivi nella cellula un gene maestro della staminalità tumorale, chiamato TAZ.
TAZ era già noto ai ricercatori: è un gene che durante lo sviluppo di un organo controlla le sue dimensioni e animali che per difetti genetici nascono con troppo TAZ sviluppano organi giganteschi.
Lo stesso meccanismo viziato che può portare al processo di crescita di un tumore e la proliferazione delle metastasi, versione stonata di quella danza armoniosa che guida invece lo sviluppo embrionale.
La scoperta apre nuove prospettive terapeutiche: in futuro, grazie a farmaci mirati e anticorpi monoclonali sarà possibile colpire con un unico vettore sia Wnt che TAZ e arrestare, quindi, lo sviluppo della malattia.
venerdì 21 dicembre 2012
Cancer Study Overturns Current Thinking About Gene Activation
From Science Daily website (see original article).
Dec. 13, 2012 — A new Australian study led by Professor Susan Clark from Sydney's Garvan Institute of Medical Research shows that large regions of the genome -- amounting to roughly 2% -- are epigenetically activated in prostate cancer.
Regions activated contain many prostate cancer-specific genes, including PSA (prostate specific antigen) and PCA3, the most common prostate cancer markers.
Until now, these genes were not known to be regulated epigenetically.
A previous study from Professor Clark's lab showed that similarly large regions of the prostate cancer genome are also epigenetically silenced, demonstrating a structured rearrangement of the cancer epigenome.
Epigenetics looks at biochemical changes that affect how the genome is organised in the cell nucleus, which in turn controls how genes are expressed.
Attachment or detachment of certain molecules can literally open or close DNA's structure, allowing a gene to be expressed if the structure is opened, and silenced if the structure is closed.
Among other aspects of epigenetic activation, the new study shows that the epigenetic process known as 'methylation' can activate genes, often by changing the gene start site, overturning the prevailing dogma that DNA methylation can only silence genes.
The findings as a whole have extensive ramifications for cancer diagnosis and treatment, including epigenetic-based gene therapies, as they require the targeting of domains of genes, as opposed to single genes.
PhD student Saul Bert and Professor Clark used gene expression profiling data and genome-wide sequencing technology from prostate tumour cells to determine which parts of the genome were epigenetically activated in prostate cancer.
They then examined the mechanisms behind activation, publishing their findings in the international journal Cancer Cell.
DNA is made up of building blocks of nucleic acid known as 'base pairs', specifically guanine-cytosine (GC) and adenine-thymine (AT). Unlike other parts of the genome, there are dense clusters of CG pairs very close to gene start sites.
These CG clusters, known as 'CpG islands', are where methylation occurs.
"When I started my PhD, we were looking to see if there was loss of methylation at CpG islands, causing gene activation in cancer," said Saul Bert.
"We took a whole genome approach, looking at all the gene transcription start sites that included CpG islands.
What we saw surprised us, because we saw gene activation at hypermethylated sites -- that went against current thinking.
"We went on to show in the lab that if you methylate CpG islands that are very close to transcription start sites, but not exactly on top of them, then it's possible to turn genes on.
"While the realisation that methylation can trigger gene activation represents a paradigm shift in thinking, our other finding -- that the prostate cancer genome contains domains that harbour multiple gene families, tumour related genes, microRNAs and cancer biomarkers -- is equally important.
These domains are simultaneously switched on through significant epigenetic remodelling.
"In this study, we identified 35 domains including 251 genes. While the genes may seem to be functionally unrelated, their coordinated regulation in the cancer genome suggests the presence of epigenetic 'master controllers' that can switch on or off very large regions of DNA."
Project leader Professor Clark believes the study will have a significant impact on our understanding of diagnostic tests and on chemotherapy treatment.
"What we are seeing in prostate cancer would apply to other cancers.
The big new finding is about the ways in which neighbouring genes are being co-ordinately activated in cancer," said Professor Clark.
"The increased expression is not just due to genetic amplification -- but we now show is also due to unraveling of the cancer genome.
"We need to understand this process more deeply to determine the impact of current epigenetic therapies that are aimed at promoting gene activation rather than suppressing oncogene expression."
Dec. 13, 2012 — A new Australian study led by Professor Susan Clark from Sydney's Garvan Institute of Medical Research shows that large regions of the genome -- amounting to roughly 2% -- are epigenetically activated in prostate cancer.
Regions activated contain many prostate cancer-specific genes, including PSA (prostate specific antigen) and PCA3, the most common prostate cancer markers.
Until now, these genes were not known to be regulated epigenetically.
A previous study from Professor Clark's lab showed that similarly large regions of the prostate cancer genome are also epigenetically silenced, demonstrating a structured rearrangement of the cancer epigenome.
Epigenetics looks at biochemical changes that affect how the genome is organised in the cell nucleus, which in turn controls how genes are expressed.
Attachment or detachment of certain molecules can literally open or close DNA's structure, allowing a gene to be expressed if the structure is opened, and silenced if the structure is closed.
Among other aspects of epigenetic activation, the new study shows that the epigenetic process known as 'methylation' can activate genes, often by changing the gene start site, overturning the prevailing dogma that DNA methylation can only silence genes.
The findings as a whole have extensive ramifications for cancer diagnosis and treatment, including epigenetic-based gene therapies, as they require the targeting of domains of genes, as opposed to single genes.
PhD student Saul Bert and Professor Clark used gene expression profiling data and genome-wide sequencing technology from prostate tumour cells to determine which parts of the genome were epigenetically activated in prostate cancer.
They then examined the mechanisms behind activation, publishing their findings in the international journal Cancer Cell.
DNA is made up of building blocks of nucleic acid known as 'base pairs', specifically guanine-cytosine (GC) and adenine-thymine (AT). Unlike other parts of the genome, there are dense clusters of CG pairs very close to gene start sites.
These CG clusters, known as 'CpG islands', are where methylation occurs.
"When I started my PhD, we were looking to see if there was loss of methylation at CpG islands, causing gene activation in cancer," said Saul Bert.
"We took a whole genome approach, looking at all the gene transcription start sites that included CpG islands.
What we saw surprised us, because we saw gene activation at hypermethylated sites -- that went against current thinking.
"We went on to show in the lab that if you methylate CpG islands that are very close to transcription start sites, but not exactly on top of them, then it's possible to turn genes on.
"While the realisation that methylation can trigger gene activation represents a paradigm shift in thinking, our other finding -- that the prostate cancer genome contains domains that harbour multiple gene families, tumour related genes, microRNAs and cancer biomarkers -- is equally important.
These domains are simultaneously switched on through significant epigenetic remodelling.
"In this study, we identified 35 domains including 251 genes. While the genes may seem to be functionally unrelated, their coordinated regulation in the cancer genome suggests the presence of epigenetic 'master controllers' that can switch on or off very large regions of DNA."
Project leader Professor Clark believes the study will have a significant impact on our understanding of diagnostic tests and on chemotherapy treatment.
"What we are seeing in prostate cancer would apply to other cancers.
The big new finding is about the ways in which neighbouring genes are being co-ordinately activated in cancer," said Professor Clark.
"The increased expression is not just due to genetic amplification -- but we now show is also due to unraveling of the cancer genome.
"We need to understand this process more deeply to determine the impact of current epigenetic therapies that are aimed at promoting gene activation rather than suppressing oncogene expression."
giovedì 6 dicembre 2012
Il sistema nervoso parasimpatico
Il sistema nervoso parasimpatico si distingue in due sezioni: craniale e sacrale.
La sezione craniale è costituita da neuroni pregangliari situati nel tronco dell’encefalo, i cui cilindrassi raggiungono la periferia attraverso il III, VII, IX, X e XI paio di n. cranici.
Provvede, così, all’innervazione per la secrezione delle ghiandole lacrimali, sottolinguali e sottomascellari (n. intermediario di Wrisberg) e per la vasodilatazione; all’innervazione secretoria della ghiandola parotide (IX paio) e delle ghiandole faringee; all’innervazione delle fibre muscolari lisce dell’esofago (plesso faringeo), dei bronchi e dei polmoni (plesso bronchiale), del muscolo cardiaco (plesso cardiaco), dello stomaco (plesso gastrico), del fegato e della cistifellea (plesso epatico), di duodeno, pancreas, intestino fino al colon trasverso (plesso celiaco), con associata funzione vasoattiva.
La sezione sacrale è costituita da neuroni pregangliari posti alla base delle corna anteriori del midollo sacrale, i cui cilindrassi escono attraverso le radici anteriori II, III e IV sacrali. I neuroni postgangliari sono i gangli del plesso ipogastrico; le fibre postgangliari sono i nervi pelvici.
In particolare, le fibre postgangliari portano impulsi motori per il colon discendente, il retto, l’ano, la vescica e alcuni muscoli genitali esterni; impulsi inibitori per gli sfinteri interni dell’ano, della vescica e dell’uretra; impulsi secretori per la prostata, le ghiandole di Bartolini e Cowper; impulsi vasodilatatori per il retto, l’ano e i genitali esterni. Il sistema parasimpatico utilizza per la trasmissione sinaptica nei gangli, nelle fibre pregangliari e nelle fibre postgangliari, l’acetilcolina. I recettori per l’acetilcolina sono indicati come muscarinici e nicotinici, a seconda che mimino rispettivamente l’azione della muscarina o della nicotina.
I recettori postgangliari sono muscarinici; a livello gangliare e a livello muscolare i recettori sono di tipo nicotinico.
La sezione craniale è costituita da neuroni pregangliari situati nel tronco dell’encefalo, i cui cilindrassi raggiungono la periferia attraverso il III, VII, IX, X e XI paio di n. cranici.
Provvede, così, all’innervazione per la secrezione delle ghiandole lacrimali, sottolinguali e sottomascellari (n. intermediario di Wrisberg) e per la vasodilatazione; all’innervazione secretoria della ghiandola parotide (IX paio) e delle ghiandole faringee; all’innervazione delle fibre muscolari lisce dell’esofago (plesso faringeo), dei bronchi e dei polmoni (plesso bronchiale), del muscolo cardiaco (plesso cardiaco), dello stomaco (plesso gastrico), del fegato e della cistifellea (plesso epatico), di duodeno, pancreas, intestino fino al colon trasverso (plesso celiaco), con associata funzione vasoattiva.
La sezione sacrale è costituita da neuroni pregangliari posti alla base delle corna anteriori del midollo sacrale, i cui cilindrassi escono attraverso le radici anteriori II, III e IV sacrali. I neuroni postgangliari sono i gangli del plesso ipogastrico; le fibre postgangliari sono i nervi pelvici.
In particolare, le fibre postgangliari portano impulsi motori per il colon discendente, il retto, l’ano, la vescica e alcuni muscoli genitali esterni; impulsi inibitori per gli sfinteri interni dell’ano, della vescica e dell’uretra; impulsi secretori per la prostata, le ghiandole di Bartolini e Cowper; impulsi vasodilatatori per il retto, l’ano e i genitali esterni. Il sistema parasimpatico utilizza per la trasmissione sinaptica nei gangli, nelle fibre pregangliari e nelle fibre postgangliari, l’acetilcolina. I recettori per l’acetilcolina sono indicati come muscarinici e nicotinici, a seconda che mimino rispettivamente l’azione della muscarina o della nicotina.
I recettori postgangliari sono muscarinici; a livello gangliare e a livello muscolare i recettori sono di tipo nicotinico.
Il nervo vago e il cuore
In caso di mancata innervazione del ramo destro del nervo vago parasimpatico al nodo sino-atriale provoca delle tachicardie, mentre se viene a mancare quello sinistro, manca l’innervazione al nodo atrio-ventricolare e di conseguenza crea aritmie.
Riparabili i danni dell'infarto
La rigenerazione del cuore dopo un infarto è una prospettiva possibile e concreta grazie alla scoperta di un gruppo di ricercatori del Centro internazionale di ingegneria genetica e biotecnologie dell’Unido a Trieste e guidato dal professor Mauro Giacca.
La scoperta pubblicata su Nature (leggi articolo) riguarda l’identificazione di quaranta piccole molecole di Rna, le quali iniettate nel cuore sono in grado di risvegliare e attivare le cellule dormienti di una parte danneggiata da un infarto del miocardio, ad esempio, rigenerandole, e guarendo quindi senza lasciare cicatrice alcuna.
PROSSIMO FARMACO
Il gruppo di Giacca stava lavorando da una decina d’anni a questo obiettivo e da un paio d’anni era iniziata l’identificazione dei microRna codificati dal genoma umano.
Una volta trovati sono iniziate le sperimentazioni su topi, ratti e cellule umane in provetta dimostrando di funzionare come previsto.
«Ora continueremo le ricerche - precisa Giacca -, per arrivare come obiettivo alla generazione di un farmaco che, iniettato nel cuore danneggiato, possa facilmente innescare la ricostruzione.
Ed è un obiettivo concreto e può essere anche molto vicino».
Nel mondo ogni anno vi sono 17 milioni di vittime per malattie cardiache, l’80 per cento delle quali nei Paesi in via sviluppo.
La prospettiva dunque offerta dal risultato triestino è tremendamente importante.
mercoledì 5 dicembre 2012
Brain Inflammation Likely Key Initiator to Prion and Parkinson's Disease
From Science Daily website (see original article).
ScienceDaily (Nov. 29, 2012) — In a recent publication, researchers of the Computational Biology group at the Luxembourg Centre for Systems Biomedicine showed that neuro-inflammation plays a crucial role in initiating prion disease.
Prion diseases represent a family of neurodegenerative disorders associated with the loss of brain cells and caused by proteins called prions (derived from ‘protein’ and ‘infection’).
The diseases are found in both humans and animals, such as Creutzfeld-Jakob disease and mad cow disease respectively.
Although mostly harmless, prions can transform into infectious agents, which accumulate in the brain and destroy the nervous tissue.
But how exactly does the accumulation of prions cause destruction of the brain? “Understanding the process by which prions destroy neurons is critical for finding a cure for prion disease”, says Isaac Crespo, first author of the publication.
He and his colleagues tackled this question with a computational approach: they ran their own computer programmes on experimental data generated by other research groups, and identified a set of 16 proteins that seems to control the onset of the disease.
Interestingly, almost all of these proteins have known functions in neuro-inflammation.
“What we consider remarkable and constitutes our main finding, is the key role that neuro-inflammation plays in initiating prion disease.
This finding is not only relevant for prion diseases, but also for other ‘protein misfolding diseases’ such as Parkinson’s and Alzheimer diseases” says Prof. Dr. Antonio del Sol, group leader of the Computational Biology group.
Since its publication on October 15th, Crespo’s paper was accessed so frequently, that it received the mark ‘Highly Accessed’, only awarded to articles that are downloaded very frequently.
The strong interest that scientists are showing for these research findings reflects the urgency with which researchers are trying to understand prion diseases for which there is no cure until today.
ScienceDaily (Nov. 29, 2012) — In a recent publication, researchers of the Computational Biology group at the Luxembourg Centre for Systems Biomedicine showed that neuro-inflammation plays a crucial role in initiating prion disease.
Prion diseases represent a family of neurodegenerative disorders associated with the loss of brain cells and caused by proteins called prions (derived from ‘protein’ and ‘infection’).
The diseases are found in both humans and animals, such as Creutzfeld-Jakob disease and mad cow disease respectively.
Although mostly harmless, prions can transform into infectious agents, which accumulate in the brain and destroy the nervous tissue.
But how exactly does the accumulation of prions cause destruction of the brain? “Understanding the process by which prions destroy neurons is critical for finding a cure for prion disease”, says Isaac Crespo, first author of the publication.
He and his colleagues tackled this question with a computational approach: they ran their own computer programmes on experimental data generated by other research groups, and identified a set of 16 proteins that seems to control the onset of the disease.
Interestingly, almost all of these proteins have known functions in neuro-inflammation.
“What we consider remarkable and constitutes our main finding, is the key role that neuro-inflammation plays in initiating prion disease.
This finding is not only relevant for prion diseases, but also for other ‘protein misfolding diseases’ such as Parkinson’s and Alzheimer diseases” says Prof. Dr. Antonio del Sol, group leader of the Computational Biology group.
Since its publication on October 15th, Crespo’s paper was accessed so frequently, that it received the mark ‘Highly Accessed’, only awarded to articles that are downloaded very frequently.
The strong interest that scientists are showing for these research findings reflects the urgency with which researchers are trying to understand prion diseases for which there is no cure until today.
martedì 4 dicembre 2012
Metabolic Protein Launches Sugar Feast That Nurtures Brain Tumors
From Science Daily website (see original article).
ScienceDaily (Nov. 26, 2012) — Researchers at The University of Texas MD Anderson Cancer Center have tracked down a cancer-promoting protein's pathway into the cell nucleus and discovered how, once there, it fires up a glucose metabolism pathway on which brain tumors thrive.
They also found a vital spot along the protein's journey that can be attacked with a type of drug not yet deployed against glioblastoma multiforme, the most common and lethal form of brain cancer. Published online by Nature Cell Biology, the paper further illuminates the importance of pyruvate kinase M2 (PKM2) in cancer development and progression.
"PKM2 is very active during infancy, when you want rapid cell growth, and eventually it turns off. Tumor cells turn PKM2 back on -- it's overexpressed in many types of cancer," said Zhimin Lu, M.D., Ph.D., the paper's senior author and an associate professor in MD Anderson's Department of Neuro-Oncology.
Lu and colleagues showed earlier this year that PKM2 in the nucleus also activates a variety of genes involved in cell division. The latest paper shows how it triggers aerobic glycolysis, processing glucose into energy, also known as the Warburg effect, upon which many types of solid tumors rely to survive and grow.
"PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways. PKM2 could be an Achilles' heel for cancer."
By pinpointing the complicated steps necessary for PKM2 to penetrate the nucleus, Lu and colleagues found a potentially druggable target that could keep the protein locked in the cell's cytoplasm.
MEK, ERK emerge as targets
The process begins when the epidermal growth factor connects to its receptor on the cell surface.
This leads to:
* Activation of the MEK protein, which in turn activates ERK.
* ERK sticking a phosphate group to a specific spot on PKM2.
* Phosphorylation priming PKM2 for a series of steps that culminate in its binding to the protein importin, which lives up to its name by taking PKM2 through the nuclear membrane.
Once in the nucleus, the team showed that PKM2 activates two genes crucial to aerobic glycolysis and another that splices PKM RNA to make even more PKM2.
An experiment applying several kinase-inhibiting drugs to human glioblastoma cell lines showed that only a MEK/ERK inhibitor prevented EGF-induced smuggling of PKM2 into the nucleus. ERK activation then is mandatory for PKM2 to get into the nucleus.
"MEK/ERK inhibitors have not been tried yet in glioblastoma multiforme," Lu said. Phosporylated PKM2 is a potential biomarker to identify patients who are candidates for MEK/ERK inhibitors once those drugs are developed.
MEK inhibitor blocks tumor growth
The researchers also found that the two glycolysis genes activated by PKM2, called GLUT1 and LDHA, are required for glucose consumption and conversion of pyruvate to lactate, crucial factors in the Warburg Effect. Depleting PKM2 in tumor cell lines reduced glucose consumption and lactate production.
In mice, depleting PKM2 blocked the growth of brain tumors. Re-expressing the wild type protein caused tumors to grow. However, re-expression of a PKM2 mutant protein that lost its ability to get into the nucleus failed to promote tumor formation. Experiments in human glioblastoma cell lines showed the same effect.
Injecting the MEK inhibitor selumetinib into tumors inhibited tumor growth, reduced ERK phosphorylation, PKM2 expression and lactate production in mice. In 48 human tumor samples, the team found that activity of EGFR, ERK1/2 and PKM2 were strongly correlated.
Cause of PKM2 overexpression
Lu and colleagues also published a paper in Molecular Cell that revealed a mechanism for overexpression of PKM2 in glioblastoma. They found that EGF receptor activation turns on NF-KB, which leads to a series of events culminating in PKM2 gene activation.
PKM2 levels were measured in tumor samples from 55 glioblastoma patients treated with standard of care surgery, radiation and chemotherapy. The 20 with low PKM2 expression had a median survival of 34.5 months, compared to 13.6 months for the 35 patients with high levels of PKM2.
Level of PKM2 expression in 27 low-grade astrocytomas was about half of the expression found in higher grade glioblastomas.
"In these two papers, we show how PKM2 is overexpressed in tumors, how it gets into the nucleus, that nuclear entry is essential to tumor development, and identified potential drugs and a biomarker that could usefully treat people," Lu said.
Co-authors of the Nature Cell Biology paper are first author Weiwei Yang, Ph.D., Yanhua Zheng, Ph.D., Yan Xia, Ph.D., and Haitao Ji, Ph.D., of MD Anderson's Department of Neuro-Oncology and Brain Tumor Center; Xiaomin Chen, Ph.D., of MD Anderson's Department of Biochemistry and Molecular Biology; Ken Aldape, M.D., MD Anderson's Department of Pathology; Fang Guo, Ph.D., Nanomedicine Center, Shanghai Research Institute, China Academy of Science; Costas Lyssiotis, Ph.D., and Lewis Cantley, Ph.D., Beth Israel Deaconess Medical Center, Harvard Medical School.
This research was funded by grants from the National Institutes of Health (numbers 2RO1CA109035, RO1GM068566 and RO1GM56302), MD Anderson's Cancer Center Support Grant (CA16672) from the National Cancer Institute; and a research grant from the Cancer Prevention and Research Institute of Texas.
ScienceDaily (Nov. 26, 2012) — Researchers at The University of Texas MD Anderson Cancer Center have tracked down a cancer-promoting protein's pathway into the cell nucleus and discovered how, once there, it fires up a glucose metabolism pathway on which brain tumors thrive.
They also found a vital spot along the protein's journey that can be attacked with a type of drug not yet deployed against glioblastoma multiforme, the most common and lethal form of brain cancer. Published online by Nature Cell Biology, the paper further illuminates the importance of pyruvate kinase M2 (PKM2) in cancer development and progression.
"PKM2 is very active during infancy, when you want rapid cell growth, and eventually it turns off. Tumor cells turn PKM2 back on -- it's overexpressed in many types of cancer," said Zhimin Lu, M.D., Ph.D., the paper's senior author and an associate professor in MD Anderson's Department of Neuro-Oncology.
Lu and colleagues showed earlier this year that PKM2 in the nucleus also activates a variety of genes involved in cell division. The latest paper shows how it triggers aerobic glycolysis, processing glucose into energy, also known as the Warburg effect, upon which many types of solid tumors rely to survive and grow.
"PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways. PKM2 could be an Achilles' heel for cancer."
By pinpointing the complicated steps necessary for PKM2 to penetrate the nucleus, Lu and colleagues found a potentially druggable target that could keep the protein locked in the cell's cytoplasm.
MEK, ERK emerge as targets
The process begins when the epidermal growth factor connects to its receptor on the cell surface.
This leads to:
* Activation of the MEK protein, which in turn activates ERK.
* ERK sticking a phosphate group to a specific spot on PKM2.
* Phosphorylation priming PKM2 for a series of steps that culminate in its binding to the protein importin, which lives up to its name by taking PKM2 through the nuclear membrane.
Once in the nucleus, the team showed that PKM2 activates two genes crucial to aerobic glycolysis and another that splices PKM RNA to make even more PKM2.
An experiment applying several kinase-inhibiting drugs to human glioblastoma cell lines showed that only a MEK/ERK inhibitor prevented EGF-induced smuggling of PKM2 into the nucleus. ERK activation then is mandatory for PKM2 to get into the nucleus.
"MEK/ERK inhibitors have not been tried yet in glioblastoma multiforme," Lu said. Phosporylated PKM2 is a potential biomarker to identify patients who are candidates for MEK/ERK inhibitors once those drugs are developed.
MEK inhibitor blocks tumor growth
The researchers also found that the two glycolysis genes activated by PKM2, called GLUT1 and LDHA, are required for glucose consumption and conversion of pyruvate to lactate, crucial factors in the Warburg Effect. Depleting PKM2 in tumor cell lines reduced glucose consumption and lactate production.
In mice, depleting PKM2 blocked the growth of brain tumors. Re-expressing the wild type protein caused tumors to grow. However, re-expression of a PKM2 mutant protein that lost its ability to get into the nucleus failed to promote tumor formation. Experiments in human glioblastoma cell lines showed the same effect.
Injecting the MEK inhibitor selumetinib into tumors inhibited tumor growth, reduced ERK phosphorylation, PKM2 expression and lactate production in mice. In 48 human tumor samples, the team found that activity of EGFR, ERK1/2 and PKM2 were strongly correlated.
Cause of PKM2 overexpression
Lu and colleagues also published a paper in Molecular Cell that revealed a mechanism for overexpression of PKM2 in glioblastoma. They found that EGF receptor activation turns on NF-KB, which leads to a series of events culminating in PKM2 gene activation.
PKM2 levels were measured in tumor samples from 55 glioblastoma patients treated with standard of care surgery, radiation and chemotherapy. The 20 with low PKM2 expression had a median survival of 34.5 months, compared to 13.6 months for the 35 patients with high levels of PKM2.
Level of PKM2 expression in 27 low-grade astrocytomas was about half of the expression found in higher grade glioblastomas.
"In these two papers, we show how PKM2 is overexpressed in tumors, how it gets into the nucleus, that nuclear entry is essential to tumor development, and identified potential drugs and a biomarker that could usefully treat people," Lu said.
Co-authors of the Nature Cell Biology paper are first author Weiwei Yang, Ph.D., Yanhua Zheng, Ph.D., Yan Xia, Ph.D., and Haitao Ji, Ph.D., of MD Anderson's Department of Neuro-Oncology and Brain Tumor Center; Xiaomin Chen, Ph.D., of MD Anderson's Department of Biochemistry and Molecular Biology; Ken Aldape, M.D., MD Anderson's Department of Pathology; Fang Guo, Ph.D., Nanomedicine Center, Shanghai Research Institute, China Academy of Science; Costas Lyssiotis, Ph.D., and Lewis Cantley, Ph.D., Beth Israel Deaconess Medical Center, Harvard Medical School.
This research was funded by grants from the National Institutes of Health (numbers 2RO1CA109035, RO1GM068566 and RO1GM56302), MD Anderson's Cancer Center Support Grant (CA16672) from the National Cancer Institute; and a research grant from the Cancer Prevention and Research Institute of Texas.
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