Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-κB activation

Yoshihiro Shirai; Tadashi Uwagawa; Hiroaki Shiba; Yohta Shimada; Takashi Horiuchi; Nobuhiro Saito; Kenei Furukawa; Toya Ohashi; Katsuhiko Yanaga

doi:10.1016/j.surg.2016.12.008

Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-κB activation

Surgery. 2017 Jun;161(6):1675-1682. doi: 10.1016/j.surg.2016.12.008. Epub 2017 Jan 13.

Authors

Yoshihiro Shirai¹, Tadashi Uwagawa², Hiroaki Shiba³, Yohta Shimada⁴, Takashi Horiuchi⁵, Nobuhiro Saito⁵, Kenei Furukawa³, Toya Ohashi⁴, Katsuhiko Yanaga³

Affiliations

¹ Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan. Electronic address: shirai@jikei.ac.jp.
² Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Clinical Oncology and Hematology, and Department of Internal Medicine, The Jikei University, School of Medicine, Tokyo, Japan.
³ Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan.
⁴ Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
⁵ Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.

PMID: 28094003
DOI: 10.1016/j.surg.2016.12.008

Abstract

Background: Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer.

Methods: A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4 weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured in vitro under preconditioning with thrombin or epidermal growth factor.

Results: Tumor growth was suppressed by recombinant thrombomodulin (P < .05). Recombinant thrombomodulin inhibited the expression of IκB kinase β (P < .05) and pIκBα (P < .01), as well as the activation of nuclear factor-kappa B NF-κB (P < .001). Furthermore, recombinant thrombomodulin inhibited thrombin-induced protease activate receptor 1 and nuclear factor-kappa B activation in vitro (P < .05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P < .01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P < .05). No obvious adverse effects were observed.

Conclusion: Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biopsy, Needle
Disease Models, Animal
Gene Expression Regulation, Neoplastic / drug effects*
Humans
I-kappa B Kinase / drug effects
I-kappa B Kinase / genetics*
Immunohistochemistry
Injections, Intraperitoneal
Male
Mice
Mice, Inbred BALB C
NF-kappa B / antagonists & inhibitors
Neoplasm Transplantation
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / pathology*
Random Allocation
Reference Values
Signal Transduction / drug effects
Thrombomodulin / administration & dosage*

Substances

NF-kappa B
Thrombomodulin
I-kappa B Kinase