Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27(Kip1)-dependent G1/S cell cycle arrest in conjunction with NF-kappaB activation
Φόρτωση...
Ημερομηνία
Συγγραφείς
Batsi, C.
Markopoulou, S.
Kontargiris, E.
Charalambous, C.
Thomas, C.
Christoforidis, S.
Kanavaros, P.
Constantinou, A. I.
Marcu, K. B.
Kolettas, E.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Biochem Pharmacol
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
2-Methoxyestradiol (2-ME2) induces leukemia cells to undergo apoptosis in association with Bcl-2 inactivation but the mechanisms whereby Bcl-2 contributes to protection against programmed cell death in this context remain unclear. Here we showed that 2-ME2 inhibited the proliferation of Jurkat leukemia cells by markedly suppressing the levels of cyclins D3 and E, E2F1 and p21(Cip1/Waf1) and up-regulating p16(INK4A). Further, 2-ME2 induced apoptosis of Jurkat cells in association with down-regulation and phosphorylation of Bcl-2 (as mediated by JNK), up-regulation of Bak, activation of caspases-9 and -3 and PARP-1 cleavage. To determine the importance and mechanistic role of Bcl-2 in this process, we enforced its expression in Jurkat cells by retroviral transduction. Enforcing Bcl-2 expression in Jurkat cells abolished 2-ME2-induced apoptosis and instead produced a G1/S phase cell cycle arrest in association with markedly increased levels of p27(Kip1). Bcl-2 and p27(Kip1) were localized mainly in the nucleus in these apoptotic resistant cells. Interestingly, NF-kappaB activity and p50 levels were increased by 2-ME2 and suppression of NF-kappaB signaling reduced p27(Kip1) expression and sensitized cells to 2-ME2-induced apoptosis. Importantly, knocking-down p27(Kip1) in Jurkat Bcl-2 cells sensitized them to spontaneous and 2-ME2-induced apoptosis. Thus, Bcl-2 prevented the 2-ME2-induced apoptotic response by orchestrating a p27(Kip1)-dependent G1/S phase arrest in conjunction with activating NF-kappaB. Thus, we achieved a much better understanding of the penetrance and mechanistic complexity of Bcl-2 dependent anti-apoptotic pathways in cancer cells and why Bcl-2 inactivation is so critical for the efficacy of apoptosis and anti-proliferative inducing drugs like 2-ME2.
Περιγραφή
Λέξεις-κλειδιά
Apoptosis/*drug effects, Cell Cycle/drug effects/genetics, Cyclin-Dependent Kinase Inhibitor p21/genetics, Cyclin-Dependent Kinase Inhibitor p27/genetics, Cyclin-Dependent Kinases/antagonists & inhibitors, Estradiol/*analogs & derivatives/pharmacology, G1 Phase/drug effects/*physiology, Humans, Jurkat Cells/cytology/*drug effects, NF-kappa B/*physiology, Proto-Oncogene Proteins c-bcl-2/*physiology, S Phase/drug effects/*physiology
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/19447221
http://ac.els-cdn.com/S0006295209001920/1-s2.0-S0006295209001920-main.pdf?_tid=dfc27659d323fd218c69e2c87b80e443&acdnat=1332999304_2a86e691afcf041d1042e826a0711e53
http://ac.els-cdn.com/S0006295209001920/1-s2.0-S0006295209001920-main.pdf?_tid=dfc27659d323fd218c69e2c87b80e443&acdnat=1332999304_2a86e691afcf041d1042e826a0711e53
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής