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

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 neede...

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Main Authors:	Yoshida, Masaki, Miyasaka, Yoshihiro, Ohuchida, Kenoki, Okumura, Takashi, Zheng, Biao, Torata, Nobuhiro, Fujita, Hayato, Nabae, Toshinaga, Manabe, Tatsuya, Shimamoto, Masaya, Ohtsuka, Takao, Mizumoto, Kazuhiro, Nakamura, Masafumi
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084662/

id	pubmed-5084662
recordtype	oai_dc
spelling	pubmed-50846622016-10-31 Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model Yoshida, Masaki Miyasaka, Yoshihiro Ohuchida, Kenoki Okumura, Takashi Zheng, Biao Torata, Nobuhiro Fujita, Hayato Nabae, Toshinaga Manabe, Tatsuya Shimamoto, Masaya Ohtsuka, Takao Mizumoto, Kazuhiro Nakamura, Masafumi Original Articles 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. John Wiley and Sons Inc. 2016-09-24 2016-10 /pmc/articles/PMC5084662/ /pubmed/27487486 http://dx.doi.org/10.1111/cas.13024 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Yoshida, Masaki Miyasaka, Yoshihiro Ohuchida, Kenoki Okumura, Takashi Zheng, Biao Torata, Nobuhiro Fujita, Hayato Nabae, Toshinaga Manabe, Tatsuya Shimamoto, Masaya Ohtsuka, Takao Mizumoto, Kazuhiro Nakamura, Masafumi
spellingShingle	Yoshida, Masaki Miyasaka, Yoshihiro Ohuchida, Kenoki Okumura, Takashi Zheng, Biao Torata, Nobuhiro Fujita, Hayato Nabae, Toshinaga Manabe, Tatsuya Shimamoto, Masaya Ohtsuka, Takao Mizumoto, Kazuhiro Nakamura, Masafumi Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
author_facet	Yoshida, Masaki Miyasaka, Yoshihiro Ohuchida, Kenoki Okumura, Takashi Zheng, Biao Torata, Nobuhiro Fujita, Hayato Nabae, Toshinaga Manabe, Tatsuya Shimamoto, Masaya Ohtsuka, Takao Mizumoto, Kazuhiro Nakamura, Masafumi
author_sort	Yoshida, Masaki
title	Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
title_short	Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
title_full	Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
title_fullStr	Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
title_full_unstemmed	Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
title_sort	calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer–stromal interactions in a mouse xenograft model
description	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.
publisher	John Wiley and Sons Inc.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084662/
_version_	1613702378119233536

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

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