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 (Journal article)

Batsi, C./ Markopoulou, S./ Kontargiris, E./ Charalambous, C./ Thomas, C./ Christoforidis, S./ Kanavaros, P./ Constantinou, A. I./ Marcu, K. B./ Kolettas, E.

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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: 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
URI: http://olympias.lib.uoi.gr/jspui/handle/123456789/23528
ISSN: 1873-2968
Link: http://www.ncbi.nlm.nih.gov/pubmed/19447221
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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