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Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model

  1. Author:
    Yamamoto, Jun
    Miyake, Kentaro
    Han, Qinghong
    Tan, Yuying
    Inubushi, Sachiko
    Sugisawa, Norihiko
    Higuchi, Takashi
    Tashiro, Yoshihiko
    Nishino, Hiroto
    Homma, Yuki
    Matsuyama, Ryusei
    Chawla, Sant P
    Bouvet, Michael
    Singh,Shree Ram
    Endo, Itaru
    Hoffman, Robert M

  2. Author Address

    AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan., AntiCancer Inc, San Diego, CA, USA., AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA., Sarcoma Oncology Center, Santa Monica, CA, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov.,
    1. Year: 2020
    2. Date: NOV 1
    3. Epub Date: 2020 07 30
  2. Journal: Cancer letters
    1. 492
    2. Pages: 174-184
  4. Type of Article: Article
  5. ISSN: 0304-3835
  1. Abstract:

    Methionine addiction is a fundamental and general hallmark of cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted cancer cell increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced apoptosis, by increasing TRAIL-R2 expression in pancreatic cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer. Copyright © 2020. Published by Elsevier B.V.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.canlet.2020.07.034
  3. PMID: 32739322
  4. View record in Web of Science®
  5. WOS: 000581518000016
  6. PII : S0304-3835(20)30390-6

Library Notes

  1. Fiscal Year: FY2019-2020
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