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Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells.
Cancer Res. 1997 Mar 15; 57(6):1109-15.CR

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-xL (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, CPP32beta/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-xL cells contain Bcl-2 as well as an enforced overexpression of Bcl-xL. Immunoprecipitation studies with anti-Bcl-2 and/or anti-Bcl-x antibodies demonstrated that HL-60/Bcl-xL cells possess lower free Bax but higher levels of Bax heterodimerized to Bcl-2 and Bcl-xL. Following treatment of HL-60/Bcl-xL cells with paclitaxel, although Bcl-2 phosphorylation was observed, it was not followed by increased free Bax levels, cleavage of CPP32beta/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.

Authors+Show Affiliations

Department of Medicine, Winship Cancer Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9067280

Citation

Ibrado, A M., et al. "Bcl-xL Overexpression Inhibits Progression of Molecular Events Leading to Paclitaxel-induced Apoptosis of Human Acute Myeloid Leukemia HL-60 Cells." Cancer Research, vol. 57, no. 6, 1997, pp. 1109-15.
Ibrado AM, Liu L, Bhalla K. Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells. Cancer Res. 1997;57(6):1109-15.
Ibrado, A. M., Liu, L., & Bhalla, K. (1997). Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells. Cancer Research, 57(6), 1109-15.
Ibrado AM, Liu L, Bhalla K. Bcl-xL Overexpression Inhibits Progression of Molecular Events Leading to Paclitaxel-induced Apoptosis of Human Acute Myeloid Leukemia HL-60 Cells. Cancer Res. 1997 Mar 15;57(6):1109-15. PubMed PMID: 9067280.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human acute myeloid leukemia HL-60 cells. AU - Ibrado,A M, AU - Liu,L, AU - Bhalla,K, PY - 1997/3/15/pubmed PY - 1997/3/15/medline PY - 1997/3/15/entrez SP - 1109 EP - 15 JF - Cancer research JO - Cancer Res VL - 57 IS - 6 N2 - 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-xL (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, CPP32beta/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-xL cells contain Bcl-2 as well as an enforced overexpression of Bcl-xL. Immunoprecipitation studies with anti-Bcl-2 and/or anti-Bcl-x antibodies demonstrated that HL-60/Bcl-xL cells possess lower free Bax but higher levels of Bax heterodimerized to Bcl-2 and Bcl-xL. Following treatment of HL-60/Bcl-xL cells with paclitaxel, although Bcl-2 phosphorylation was observed, it was not followed by increased free Bax levels, cleavage of CPP32beta/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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/9067280/Bcl_xL_overexpression_inhibits_progression_of_molecular_events_leading_to_paclitaxel_induced_apoptosis_of_human_acute_myeloid_leukemia_HL_60_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9067280 DB - PRIME DP - Unbound Medicine ER -