Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model

Masaki Yoshida, Yoshihiro Miyasaka, Kenoki Ouchida, Takashi Okumura, Biao Zheng, Nobuhiro Torata, Hayato Fujita, Toshinaga Nabae, Tatsuya Manabe, Masaya Shimamoto, Ohtsuka Takao, Kazuhiro Mizumoto, Masafumi Nakamura

Research output: Contribution to journalArticle

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Abstract

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer–stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer–stromal interaction.

Original languageEnglish
Pages (from-to)1443-1452
Number of pages10
JournalCancer Science
Volume107
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

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Pancreatic Neoplasms
Heterografts
Pancreatic Stellate Cells
Calpain
Tumor Burden
calpain inhibitors
calpeptin
Neoplasms
Polymerase Chain Reaction
Messenger RNA
Nude Mice
Antineoplastic Agents
Fibrosis
Fibroblasts
Cell Proliferation
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model. / Yoshida, Masaki; Miyasaka, Yoshihiro; Ouchida, Kenoki; Okumura, Takashi; Zheng, Biao; Torata, Nobuhiro; Fujita, Hayato; Nabae, Toshinaga; Manabe, Tatsuya; Shimamoto, Masaya; Takao, Ohtsuka; Mizumoto, Kazuhiro; Nakamura, Masafumi.

In: Cancer Science, Vol. 107, No. 10, 01.10.2016, p. 1443-1452.

Research output: Contribution to journalArticle

Yoshida, Masaki ; Miyasaka, Yoshihiro ; Ouchida, Kenoki ; Okumura, Takashi ; Zheng, Biao ; Torata, Nobuhiro ; Fujita, Hayato ; Nabae, Toshinaga ; Manabe, Tatsuya ; Shimamoto, Masaya ; Takao, Ohtsuka ; Mizumoto, Kazuhiro ; Nakamura, Masafumi. / Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model. In: Cancer Science. 2016 ; Vol. 107, No. 10. pp. 1443-1452.
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AU - Zheng, Biao

AU - Torata, Nobuhiro

AU - Fujita, Hayato

AU - Nabae, Toshinaga

AU - Manabe, Tatsuya

AU - Shimamoto, Masaya

AU - Takao, Ohtsuka

AU - Mizumoto, Kazuhiro

AU - Nakamura, Masafumi

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AB - Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer–stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer–stromal interaction.

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