Research Papers:

Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells

Reo Nozaki, Toru Kono _, Hiroki Bochimoto, Tsuyoshi Watanabe, Kaori Oketani, Yuichi Sakamaki, Naoto Okubo, Koji Nakagawa and Hiroshi Takeda

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Oncotarget. 2016; 7:70437-70446. https://doi.org/10.18632/oncotarget.11926

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Reo Nozaki1, Toru Kono1,2, Hiroki Bochimoto3, Tsuyoshi Watanabe3, Kaori Oketani1, Yuichi Sakamaki1, Naoto Okubo1, Koji Nakagawa1, Hiroshi Takeda1

1Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, Sapporo, Hokkaido, Japan

2Center for Clinical and Biomedical Research, Sapporo Higashi-Tokushukai Hospital, Sapporo, Hokkaido, Japan

3Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan

Correspondence to:

Toru Kono, email: [email protected]

Keywords: autophagy, autophagic cell death, vacuolization, colon cancer, zanthoxylum fruit

Received: February 09, 2016     Accepted: September 02, 2016     Published: September 10, 2016


Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF-7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.

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