67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis

Motofumi Kumazoe, Kaori Sugihara, Shuntaro Tsukamoto, Yuhui Huang, Yukari Tsurudome, Takashi Suzuki, Yumi Suemasu, Naoki Ueda, Shuya Yamashita, Yoonhee Kim, Koji Yamada, Hirofumi Tachibana

研究成果: ジャーナルへの寄稿記事

86 引用 (Scopus)

抄録

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCΔ/acid sphingomyelinase (PKCΔ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5(PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

元の言語英語
ページ(範囲)787-799
ページ数13
ジャーナルJournal of Clinical Investigation
123
発行部数2
DOI
出版物ステータス出版済み - 2 1 2013

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Laminin Receptors
Apoptosis
Cell Death
Neoplasms
Phosphodiesterase 5 Inhibitors
Death Domain Receptors
Bile Duct Neoplasms
Type 5 Cyclic Nucleotide Phosphodiesterases
Breast Neoplasms
Sphingomyelin Phosphodiesterase
Polyphenols
Laminin
Erectile Dysfunction
Tea
Heterografts
Uterine Cervical Neoplasms
Colorectal Neoplasms
Cell Survival
Carrier Proteins
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Kumazoe, M., Sugihara, K., Tsukamoto, S., Huang, Y., Tsurudome, Y., Suzuki, T., ... Tachibana, H. (2013). 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. Journal of Clinical Investigation, 123(2), 787-799. https://doi.org/10.1172/JCI64768

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. / Kumazoe, Motofumi; Sugihara, Kaori; Tsukamoto, Shuntaro; Huang, Yuhui; Tsurudome, Yukari; Suzuki, Takashi; Suemasu, Yumi; Ueda, Naoki; Yamashita, Shuya; Kim, Yoonhee; Yamada, Koji; Tachibana, Hirofumi.

:: Journal of Clinical Investigation, 巻 123, 番号 2, 01.02.2013, p. 787-799.

研究成果: ジャーナルへの寄稿記事

Kumazoe, M, Sugihara, K, Tsukamoto, S, Huang, Y, Tsurudome, Y, Suzuki, T, Suemasu, Y, Ueda, N, Yamashita, S, Kim, Y, Yamada, K & Tachibana, H 2013, '67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis', Journal of Clinical Investigation, 巻. 123, 番号 2, pp. 787-799. https://doi.org/10.1172/JCI64768
Kumazoe M, Sugihara K, Tsukamoto S, Huang Y, Tsurudome Y, Suzuki T その他. 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. Journal of Clinical Investigation. 2013 2 1;123(2):787-799. https://doi.org/10.1172/JCI64768
Kumazoe, Motofumi ; Sugihara, Kaori ; Tsukamoto, Shuntaro ; Huang, Yuhui ; Tsurudome, Yukari ; Suzuki, Takashi ; Suemasu, Yumi ; Ueda, Naoki ; Yamashita, Shuya ; Kim, Yoonhee ; Yamada, Koji ; Tachibana, Hirofumi. / 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. :: Journal of Clinical Investigation. 2013 ; 巻 123, 番号 2. pp. 787-799.
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abstract = "The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCΔ/acid sphingomyelinase (PKCΔ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5(PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.",
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AU - Tsurudome, Yukari

AU - Suzuki, Takashi

AU - Suemasu, Yumi

AU - Ueda, Naoki

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AU - Tachibana, Hirofumi

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