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15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation

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Abstract

While tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising new agent for the treatment of cancer, resistance to TRAIL remains a therapeutic challenge. Identifying agents to use in combination with TRAIL to enhance apoptosis in leukemia cells would increase the potential utility of this agent as a therapy for leukemia. Here, we show that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor γ (PPARγ), can sensitize TRAIL-resistant leukemic HL-60 cells to TRAIL-induced apoptosis. The sensitization to TRAIL-induced apoptosis by 15d-PGJ2 was not blocked by a PPARγ inhibitor (GW9662), suggesting a PPARγ-independent mechanism. This process was accompanied by activation of caspase-8, caspase-9, and caspase-3 and was concomitant with Bid and PARP cleavage. We observed significant decreases in XIAP, Bcl-2, and c-FLIP after cotreatment with 15d-PGJ2 and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ2 and TRAIL. Furthermore, inactivation of Akt by Akt inhibitor IV sensitized human leukemic HL-60 cells to TRAIL, indicating a key role for Akt inhibition in these events. Taken together, these findings indicate that 15d-PGJ2 may augment TRAIL-induced apoptosis in human leukemia cells by down-regulating the expression and phosphorylation of Akt.

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Acknowledgments

This work was supported by the Korea Science and Engineering Foundation through the Medical Science and Engineering Research Center for Cancer Molecular Therapy at Dong-A University.

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Authors and Affiliations

  1. Department of Biochemistry, Dong-A University College of Medicine, 3 Ga 1, Dongdaesin-Dong, Seo-Gu, Busan, 602-714, South Korea

    Hoon Han, Sung-Won Shin, Jong-Young Kwak & Joo-In Park

  2. Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan, South Korea

    Hoon Han, Sung-Won Shin, Chi-Yeon Seo, Jong-Young Kwak & Joo-In Park

  3. Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea

    Hyuk-Chan Kwon

  4. Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, South Korea

    Jin-Yeong Han

  5. Division of Basic Science, National Cancer Center Research Institute, Goyang, Gyeonggi, South Korea

    In-Hoo Kim

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  1. Hoon Han
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Han, H., Shin, SW., Seo, CY. et al. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation. Apoptosis 12, 2101–2114 (2007). https://doi.org/10.1007/s10495-007-0124-2

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