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| Bcl-x(L) overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells |
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| Author(s): Ibrado AM, Liu L, Bhalla K |
| Source: CANCER RESEARCH Volume: 57 Issue: 6 Pages: 1109-1115 Published: MAR 15 1997 |
| Times Cited: 103 References: 41 |
| Abstract: Paclitaxel has been shown to activate Raf-1 and cause phosphorylation of Bcl-2, which has been correlated with paclitaxel-induced apoptosis of cancer cells. In the present studies, we demonstrate that in human AML HL-60 cells that express Bcl-2 but little Bcl-x(L) (HL-60/neo cells), paclitaxel-induced phosphorylation of Bcl-2 is followed by increased intracellular free Bax levels. This, in turn, is followed by the cleavage and activation of the key cysteine protease, CPP32 beta/Yama, and cleavage of poly(ADP-ribose) polymerase, resulting in the DNA fragmentation of apoptosis. Cotreatment with the benzoquinone ansamycin Geldanamycin depleted Raf-1 but did not decrease Bcl-2 Levels or impair paclitaxel-induced Bcl-2 phosphorylation in HL-60/neo cells. Also, Geldanamycin did not affect paclitaxel-induced apoptosis of HL-60/neo cells. As compared to the control HL-60/neo, HL-60/Bcl-x(L) cells contain Bcl-2 as well as an enforced overexpression of Bcl-x(L). Immunoprecipitation studies with anti-Bcl-2 and/or anti-Bcl-x antibodies demonstrated that HL-60/Bcl-x(L) cells possess lower free Bax but higher levels of Bax heterodimerized to Bcl-2 and Bcl-x(L). Following treatment of HC60/Bcl-x(L) cells with paclitaxel, although Bcl-2 phosphorylation was observed, it was not followed by increased free Bax levels, cleavage of CPP32 beta/Yama and poly(ADP-ribose) polymerase, or induction of the DNA fragmentation of apoptosis. These findings indicate the order of molecular events leading to paclitaxel-induced apoptosis and show that Raf-1 may not be involved in paclitaxel-induced phosphorylation of Bcl-2 or apoptosis of HL-60 cells. |
| Document Type: Article |
| Language: English |
Addresses:
1. EMORY UNIV, SCH MED,WINSHIP CANC CTR,DIV HEMATOL ONCOL, DEPT MED, ATLANTA, GA 30322 USA |
| Publisher: AMER ASSOC CANCER RESEARCH, PUBLIC LEDGER BLDG, SUITE 816, 150 S. INDEPENDENCE MALL W., PHILADELPHIA, PA 19106 |
| Subject Category: Oncology |
| IDS Number: WN564 |
| ISSN: 0008-5472 |
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