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 PKCĪ“/ acid sphingomyelinase (PKCĪ“/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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Authors | Motofumi Kumazoe, Kaori Sugihara, Shuntaro Tsukamoto, Yuhui Huang, Yukari Tsurudome, Takashi Suzuki, Yumi Suemasu, Naoki Ueda, Shuya Yamashita, Yoonhee Kim, Koji Yamada, Hirofumi Tachibana |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 123
Issue 2
Pg. 787-99
(Feb 2013)
ISSN: 1558-8238 [Electronic] United States |
PMID | 23348740
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Imidazoles
- Phosphodiesterase 5 Inhibitors
- Piperazines
- Receptors, Laminin
- Sulfones
- Triazines
- Vardenafil Dihydrochloride
- Catechin
- epigallocatechin gallate
- Cyclic Nucleotide Phosphodiesterases, Type 5
- Caspases
- Cyclic GMP
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Topics |
- Animals
- Apoptosis
(drug effects, physiology)
- Caspases
(metabolism)
- Catechin
(analogs & derivatives, pharmacology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cyclic GMP
(metabolism)
- Cyclic Nucleotide Phosphodiesterases, Type 5
(metabolism)
- Female
- Humans
- Imidazoles
(pharmacology)
- Male
- Membrane Potential, Mitochondrial
(drug effects)
- Mice
- Mice, Inbred BALB C
- Molecular Weight
- Multiple Myeloma
(drug therapy, metabolism, pathology)
- Neoplasms
(drug therapy, metabolism, pathology)
- Phosphodiesterase 5 Inhibitors
(pharmacology)
- Piperazines
(pharmacology)
- Receptors, Laminin
(chemistry, metabolism)
- Signal Transduction
- Sulfones
(pharmacology)
- Triazines
(pharmacology)
- Vardenafil Dihydrochloride
- Xenograft Model Antitumor Assays
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