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

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.

• 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)

Chemical References

• Imidazoles
• Phosphodiesterase 5 Inhibitors
• Piperazines
• Receptors, Laminin
• Sulfones
• Triazines
• Vardenafil Dihydrochloride
• Catechin
• epigallocatechin gallate
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Caspases
• Cyclic GMP

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