67-kDa Laminin Receptor Increases cGMP to Induce Cancer-Selective Apoptosis

J Clin Invest. 2013 Feb;123(2):787-99. doi: 10.1172/JCI64768. Epub 2013 Jan 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspases / metabolism
  • Catechin / analogs & derivatives
  • Catechin / 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
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Piperazines / pharmacology
  • Receptors, Laminin / chemistry
  • Receptors, Laminin / metabolism*
  • Signal Transduction
  • Sulfones / pharmacology
  • Triazines / pharmacology
  • Vardenafil Dihydrochloride
  • Xenograft Model Antitumor Assays

Substances

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