la protéine Tribbles dans l'AML

Apr. 17, 2013 — A new, pre-clinical study by researchers at Virginia Commonwealth University Massey Cancer Center suggests that a novel drug combination could lead to profound leukemia cell death by disrupting the function of two major pro-survival proteins. The effectiveness of the therapy lies in its ability to target a pro-survival cell signaling pathway known as PI3K/AKT/mTOR, upon which the leukemia cells have become dependent.

Une étude pré-clinique suggère qu'une combinaison de médicaments pourrait conduire à beaucoup de mort de cellules cancéreuses en interrompant les fonctions de 2 protéines importantes. L'efficacité de cette thérapie est dans sa capacité à cibler un chemin cellulaire de survie connu comme PI3K/akt/mTOR, duquel les cellules leucémiques sont dépendantes.

In the study, published in the journal Cancer Research, researchers combined the drug ABT-737 with another agent BEZ235. ABT-737 targets proteins known as B-cell lymphoma 2 (Bcl-2) and Bcl-xL, which prevent apoptosis, a form of cell suicide, in cancer cells. BEZ235 directly inhibits the PI3K/AKT/mTOR pathway, and as a result, reduces the expression of another anti-apoptotic protein known as Mcl-1, which is not targeted by ABT-737.

Dan l'étude, les chercheurs ont combiné le médicament ABT-737 avec un autre agent BEZ235. ABT-737 cible les protéines Bcl-2 et Bcl-xL qui empêchentl'apoptose, qui est une forme de suicide de la cellule cancéreuse. BEZ235 inhibe le chemin cellulaire PI3K/AKT/mTOR et comme résultat réduit l'expression d'une autre protéine anti-apoptique Mcl-1 que ne cible pas ABT-737.

Among their many functions, signaling pathways regulate biological processes required for cellular survival. The PI3K/AKT/mTOR pathway helps keep apoptosis in check, in part, by controlling the production of Mcl-1. However, the pathway can become dysregulated in cancer, and in so doing, contribute to uncontrolled tumor growth and resistance to conventional cancer therapies. It is activated in 50 to 80 percent of patients with acute myelogenous leukemia (AML), and in some, but not all cases, is associated with genetic mutations. Significantly, disabling both anti-apoptotic proteins, Bcl-2 and Bcl-xL, in conjunction with Mcl-1, caused profound cell death of leukemia cells in the test tube as well as in animal models of AML.

Parmi leurs nombreuses fonctions, les voies de signalisation régulent les processus biologiques nécessaires à la survie cellulaire. La voie de PI3K/AKT/mTOR permet de garder l'apoptose en échec, en partie, par le contrôle de la production de Mcl-1. Cependant, la voie peut devenir dérégulée dans le cancer, et, ce faisant, contribuer à la croissance de la tumeur incontrôlée et la résistance aux traitements anticancéreux conventionnels. Elle est activée dans 50 à 80 pour cent des patients atteints de leucémie myéloïde aiguë (LMA), et dans certains cas, mais pas tous, cette voie est associée à des mutations génétiques. De manière significative, la désactivation de ces deux protéines anti-apoptotiques, Bcl-2 et Bcl-XL, en collaboration avec Mcl-1, cause la mort cellulaire profonde des cellules leucémiques dans le tube à essai, ainsi que dans des modèles animaux d'AML.

"This study builds on many years of work in our laboratory investigating the mechanisms that regulate apoptosis in human leukemia cells. To the best of our knowledge, it is the first to raise the possibility that activation of the P13K/AKT/mTOR pathway, rather than genetic mutations within the pathway, may represent the best predictor of leukemia cell responses to these targeted agents," says one of the study's key researchers Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader of Developmental Therapeutics and Cancer Cell Signaling research member at VCU Massey Cancer Center. "These findings could lead to a new therapeutic strategy for patients with AML and potentially other diseases by targeting patients whose leukemia cells display activation of a specific survival pathway."

«Cette étude s'appuie sur de nombreuses années de travail dans notre laboratoire ou l'on a étudié les mécanismes qui régulent l'apoptose dans les cellules leucémiques humaines. Au meilleur de nos connaissances, il est le premier à évoquer la possibilité que l'activation de la voie de P13K/AKT/mTOR, plutôt que des mutations génétiques dans la voie, peuvent représenter le meilleur prédicateur de la réponse des lymphocytes leucémiques à ces agents ciblés ", dit l'un des principaux chercheurs de l'étude. «Ces résultats pourraient conduire à une nouvelle stratégie thérapeutique pour les patients atteints de LAM et potentiellement d'autres maladies, en ciblant les patients dont les cellules leucémiques affichent l'activation d'une voie de survie spécifique."

Grant's team made another discovery that helped explain the new therapy's effectiveness. They found that the therapy releases and/or activates the pro-apoptotic proteins Bim, Bak and Bax, which help trigger apoptosis. Thus, in addition to disabling major pro-survival proteins, the combination therapy also helps to unleash several additional proteins that promote apoptosis.

L'équipe de Grant a fait une autre découverte qui aide à expliquer l'efficacité de la nouvelle thérapie. Ils ont trouvé que la thérapie libère ou active les protéines pro-apoptiques : Bim, Bak et Bax qui aident à initier l'apoptose. Ceci en plus de combattre des protéines pro-survie, la combinaison de molécules aide aussi à relâcher plusieurs protéines additionnelles qui promeuvent l'apoptose.

Moving forward, Grant and his team hope to work with pharmaceutical companies and the National Cancer Institute to develop strategies combining inhibitors of the PI3K/AKT/mTOR pathway with Bcl-2 family antagonists for the treatment of patients with AML.

Grant et son équipe veuent travailler avec les compagnies pharmaceutiques et le NCI pour développer des stratégies combinant des inhibiteurs de PI3K/AKT/mTOR avec des antagonistes de la famille Bcl2 pour le traitement des patients avec la LMA.

“Tribbles had never been directly linked to human malignancy,” says senior author Warren S. Pear, MD, PhD, Associate Professor of Pathology and Laboratory Medicine. “This is a new protein to human cancer and has a specific and overwhelming effect when expressed in hematopoietic stem cells, the cell type that gives rise to all elements of the blood.”

"Tribbles n'a jamais été directement lié au cancer humain" dit Warren S. Pear. "C'est une nouvelle protéine pour le cancer humain qui a un effet spécific et sérieux quand elle est exprimée dans les cellules souches du sang. les cellules qui donne tous les éléments du sang.

Three lines of evidence implicate Tribbles in AML. First, all mice engineered to express Tribbles-2 (Trib-2) in hematopoietic stem cells developed AML. They also found that Trib-2 inhibited C/EBPa, another protein that is frequently mutated in AML patients. Additionally, expression of the Tribbles protein was elevated in blood samples from AML patients, further suggesting that it contributes to AML. Overall, the findings suggest that Tribbles induces AML by inactivating the C/EBPa protein. The results were published in this week’s issue of Cancer Cell.

Il y a trois preuves qui implique Tribbles dans la leucémie AML : toutes les souris qui sont manipulées pour que soit exprimé tribbles-2 (trib-2) dans les cellules souches du sang, développent l'AML. Trib-2 inhibe aussi c/EBPa, une autre protéine qui est fréquemment muté chez les patients AML. Aussi, l'expression de Tribbles est élevé dans les prises de sang des patients atteints de AML. Finalement ces découvertes suggèrent que Tribbles induit l'AML en inactivant la protéine C/EBP. Les résultats étaient publié dans un numéro de "Cancer Cells"

AML is a malignancy that arises in white blood cells and develops when there is a defect in immature immune cells in the bone marrow. In AML, the uncontrolled, exaggerated growth and accumulation of white blood cells leads to anemia and a deficiency of normal white cells in the blood. AML is the most common type of leukemia in adults, with an estimated 10,100 new cases reported each year.

Pear, also a researcher in the Abramson Family Cancer Research Institute at Penn; first author and postdoctoral fellow Karen Keeshan, PhD; and colleagues found Tribbles by chance when looking for the molecular partners of another protein called Notch. Notch is a molecular switch of sorts, activating gene transcription in the nucleus of many types of cells, and depending on the biochemical context, turns certain pathways on and others off.

Pear and colleagues knew from fruit fly studies that the Tribbles protein was linked to cell growth and cell-fate determination and is closely related to the Tribbles gene in mammals. In fact, Tribbles is so named because, when mutated in flies, it causes cells to proliferate uncontrollably.

Accumulating evidence from several groups shows that Tribbles functions as a scaffold to bring together a complex that mediates protein degradation. Protein degradation is required for normal cellular function; however, data from the Pear lab suggests that mistakes in the expression of the Tribbles gene may lead to degradation of proteins that hold cancer in check, such as tumor suppressors. “One of our current challenges is to determine what other proteins Tribbles degrades to cause leukemia,” says Pear.

The findings in mice were also validated in a large database of human cancer patients. In a survey of gene expression in AML patients, high Tribbles expression was found in a subset of patients who had been previously characterized by defects in C/EBPa.

According to Keeshan, “C/EBPa defects have also been identified in lung cancer and other tumors, suggesting the possibility that Trib2 dysregulation may be identified in other tumors. Furthermore, linking Trib2 to human cancer adds further support to the notion that targeting the protein degradation machinery will be a useful strategy in treating malignancy.”

selon Keeshan : " Les défauts de la protéine C/EBP sont aussi identifié dans le cancer du poumon et d'autres cancers"