Document Detail

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis.
MedLine Citation:
PMID:  23348740     Owner:  NLM     Status:  MEDLINE    
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.
Motofumi Kumazoe; Kaori Sugihara; Shuntaro Tsukamoto; Yuhui Huang; Yukari Tsurudome; Takashi Suzuki; Yumi Suemasu; Naoki Ueda; Shuya Yamashita; Yoonhee Kim; Koji Yamada; Hirofumi Tachibana
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  787-99     Citation Subset:  AIM; IM    
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
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MeSH Terms
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
Imidazoles / pharmacology
Membrane Potential, Mitochondrial / drug effects
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
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Imidazoles; 0/Phosphodiesterase 5 Inhibitors; 0/Piperazines; 0/Receptors, Laminin; 0/Sulfones; 0/Triazines; 154-23-4/Catechin; 7665-99-8/Cyclic GMP; BQM438CTEL/epigallocatechin gallate; EC Nucleotide Phosphodiesterases, Type 5; EC 3.4.22.-/Caspases; UCE6F4125H/vardenafil
Comment In:
J Clin Invest. 2013 Feb 1;123(2):556-8   [PMID:  23348734 ]

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