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Bortezomib Sensitizes Human Esophageal Squamous Cell Carcinoma Cells to TRAIL-Mediated Apoptosis via Activation of Both Extrinsic and Intrinsic Apoptosis Pathways

  1. Author:
    Seki, N.
    Toh, U.
    Sayers, T. J.
    Fujii, T.
    Miyagi, M.
    Akagi, Y.
    Kusukawa, J.
    Kage, M.
    Shirouzu, K.
    Yamana, H.

  2. Author Address

    [Seki, Naoko; Toh, Uhi; Fujii, Teruhiko; Kage, Masayoshi; Yamana, Hideaki] Kurume Univ, Res Ctr Innovat Canc Therapy, Kurume, Fukuoka 8300011, Japan. [Toh, Uhi; Fujii, Teruhiko; Miyagi, Motoshi; Akagi, Yoshito; Shirouzu, Kazuo; Yamana, Hideaki] Kurume Univ, Dept Surg, Sch Med, Kurume, Fukuoka 8300011, Japan. [Kusukawa, Jingo] Kurume Univ Hosp, Dent & Oral Med Ctr, Kurume, Fukuoka, Japan. [Kage, Masayoshi] Kurume Univ Hosp, Dept Pathol, Kurume, Fukuoka, Japan. [Fujii, Teruhiko] Natl Hosp Org Kyushu Med Ctr, Fukuoka, Japan. [Sayers, Thomas J.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA.;Seki, N, Kurume Univ, Res Ctr Innovat Canc Therapy, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan.;seki_naoko@kurume-u.ac.jp
    1. Year: 2010
    2. Date: Jun
  2. Journal: Molecular Cancer Therapeutics
    1. 9
    2. 6
    3. Pages: 1842-1851
  4. Type of Article: Article
  5. ISSN: 1535-7163
  1. Abstract:

    Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive human cancers, and novel treatment modalities are required. We investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) in combination with the proteasome inhibitor bortezomib (Velcade) on human ESCC cell lines. Bortezomib enhanced the susceptibility to TRAIL in 12 of the 15 ESCC cell lines tested, although most showed low sensitivity to TRAIL as a single agent. The enhancement of TRAIL-induced apoptosis by bortezomib was caspase dependent. Increased processing of caspase-8 often accompanied enhancement of TRAIL-induced apoptosis by bortezomib. However, the increased cell surface expression of death receptors observed on bortezomib treatment did not seem to be crucial for this effect. For some ESCC, bortezomib treatment resulted in a more efficient recruitment of caspase-8 and the Fas-associated death domain to the death-inducing signaling complex. Additional downregulation of the cellular FLICE-inhibitory protein long isoform [c-FLIP(L)] could cooperate in the activation of the extrinsic pathway in some cases. For other ESCC, the crucial effect of bortezomib treatment seemed to be increased signaling via the intrinsic apoptotic pathway on subsequent exposure to TRAIL. Thus, bortezomib could sensitize ESCC to TRAIL apoptosis by multiple molecular mechanisms of action. Therefore, the combination of bortezomib and TRAIL might be a novel therapeutic strategy for ESCC patients who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. Mol Cancer Ther; 9(6); 1842-51. (C)2010 AACR.

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External Sources

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  2. DOI: 10.1158/1535-7163.mct-09-0918
  3. View record in Web of Science®
  4. WOS: 000278569200035

Library Notes

  1. Fiscal Year: FY2009-2010
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