Mesenchymal Stem Cells Promote Survival of Leukemic Cells Via Integrin-Linked Kinase (ILK)-Dependent Akt and STAT3 Activation: Implications for Leukemia Therapy.
Notice bibliographique
Résumé
Abstract The β integrins play an important role in the cell-to-cell interactions, which trigger intracellular signal transduction pathways. Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate Akt, which promotes cell survival. On the other hand, PI3K/Akt and JAK/STAT signaling pathways are also recognized as potent anti-apoptotic mediators activated by ligation of growth factor receptors. We have previously demonstrated that stroma cells protect acute promyelocytic leukemic (APL) cells from apoptosis (Tabe, Blood103:1815–1822, 2004). Here, we investigate the ability of bone marrow stroma cells to activate Akt, STAT3, and ILK signaling in leukemic cells co-cultured with stroma in low-serum conditions (0.5% FCS). Human mesenchymal stem cells (MSC), co-cultivated with APL-derived NB4 cells in direct cell-to-cell contact, partially inhibited spontaneous apoptosis and enhanced viability of NB4, while separation from stromal cells by transwell insert abrogated this supporting effect of MSC. Western blot analysis using phosphospecific antibodies demonstrated that direct cell-to-cell contact with MSC caused strong activation of Akt and STAT3 signaling in NB4 cells, which have low baseline phosphorylation of these proteins. Treatment with PI3K inhibitor LY294002 or JAK/STAT3 inhibitor (AG480) decreased both, Akt and STAT3 activation in NB4 cells, however, in cells co-cultured in direct contact with MSC the Akt and STAT3 phosphorylation levels were still significantly higher than in suspension cultures and in cells separated by transwell. These observations indicate cross-talk between PI3K/Akt and JAK/STAT pathways, and that Akt is activated independent from PI3K in NB4 cells through direct interaction with MSC. Both, LY294002 and AG480 induced apoptosis and decreased viability of suspension NB4 cells, but this effect was partially abrogated by MSC co-culture. Next, we examined the effects of these signal transduction inhibitors on MSC. MSC expressed both, phospho-Akt and phospho-Stat3, which was inhibited by LY294002 and AG480. LY294002 but not AG480 induced moderate apoptosis in MSC (annexin V positivity; MSC alone19.7 %; LY294002, 30.8%; AG480, 20.1% at 72 hours). Finally, we investigated Akt and STAT3 activation associated with ILK in NB4 cells. Treatment with ILK inhibitor KP004 (QLT Inc., Vancouver, Canada) decreased phosphorylation of Akt and STAT3 only in NB4 cells co-cultured with MSC and not in suspension cultures. The specific abrogation of MSC-mediated signaling resulted in higher induction of apoptosis in stroma co-cultured cells compared to suspension cells (annexin V positivity; KP004 treated suspension cultures 47.4±4.3%; MSC co-cultures 64.9±10.3%). These results indicate that bone marrow stroma cells support survival of leukemic cells through β integrin linked ILK, which activates Akt in a PI3K-independent manner and also stimulates STAT3. We propose that abrogation of ILK/Akt and STAT3 signaling may overcome protective effects of the bone marrow microenvironment on APL cells and thereby greatly enhance anti-leukemic therapies.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».