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Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-γ agonists induced apoptosis in human monocyte leukemia cells in vitro

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Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a transcription factor important in fat metabolism and PPAR-γ agonists were recently demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. In the present study, two PPAR-γ agonists, 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) and a synthetic PPAR-γ agonist troglitazone (TGZ), were used to investigate activated PPAR-γ-induced apoptosis on human monocyte leukemia U937 and Mono Mac 6 cells in vitro. The results showed that both U937 and Mono Mac 6 cells demonstrated constitutive activation of COX-2 expression; treatment by 15d-PGJ2 and TGZ could induce apoptosis remarkably in human monocyte leukemia cells by disruption of mitochondrial membrane potential, activation of caspase-3, and causing cleavage of the caspase substrate poly (ADP-ribose) polymerase (PARP). Further studies revealed that treatment by both 15d-PGJ2 and TGZ remarkably downregulated COX-2 expression in these two kind of monocyte leukemia cells as measured by reverse transcriptase PCR (RT-PCR) and Western blot. Furthermore, the expression of Bcl-2 and Bcl-Xl and Mcl-1 was downregulated while Bax expression was upregulated concurrently after the cells were treated by these two agonists, and no variations were found in other Bcl-2 family members such as Bak, Bid, and Bad. Taken together, our results demonstrate for the first time that downregulation of cyclooxygenase-2 expression, disruption of mitochondrial membrane potential, activation of caspase-3, downregulation of Bcl-2, Bcl-Xl, and Mcl-1, and upregulation of Bax are involved in PPAR-γ agonists-induced apoptosis in these two human monocyte leukemia cells.

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Acknowledgements

We thank Professor Wang JB for presenting microculture tetrazolium, Dr. Zhu ZY and postdoctoral fellow Liu H for help with computer analysis and presentation of data. We also thank the members of our laboratories for their insight and technical support. This work is supported by the grants from National Natural Science Foundation of China (no. 30570786).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 6000, Guangzhou, 510630, People’s Republic of China

    Jia-Jun Liu, Dong-Jun Lin, Ruo-Zhi Xiao, Xu-Dong Li, Yi He & Ren-Wei Huang

  2. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Zhongshan Road 2, Guangzhou, 510080, People’s Republic of China

    Pei-Qing Liu & Min Huang

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  1. Jia-Jun Liu
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Correspondence to Jia-Jun Liu or Pei-Qing Liu.

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Dong-Jun Lin and Jia-Jun Liu contributed equally to this study.

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Liu, JJ., Liu, PQ., Lin, DJ. et al. Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-γ agonists induced apoptosis in human monocyte leukemia cells in vitro. Ann Hematol 86, 173–183 (2007). https://doi.org/10.1007/s00277-006-0205-2

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