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.

Alterations in the Cerebellar (Phospho)Proteome of a Cyclic Guanosine Monophosphate (cGMP)-dependent Protein Kinase Knockout Mouse

“…The absence of cGKI and an increase of the cGMP level could lead to the activation of other kinases, such as PKA (47) or PKC (49). PKCII␤, indeed, in our dataset, showed high regulation at the phosphorylation level of the activation loop site (Fig.…”

Combination of Chemopreventive Agents in Nanoparticles for Cancer Prevention

“…When a PDE5-selective inhibitor, vardenafil, was also added to cultured cells, it synergized with EGCG to reduce the IC 50 of EGCG from 23.2 to 1.4 mmol/L. Such synergy was also observed in xenograft tumors (20).…”

“…A good example for showing synergistic effect between two agents was recently provided by Kumazoe and colleagues (20). These authors showed that (À)epigallocatechin 3-gallate (EGCG) activated 67-kDa laminin receptors in multiple myeloma cells.…”

Tea and human health: biomedical functions of tea active components and current issues

“…Based on previous evidence, they presented a new concept: green tea catechins as synergists with anticancer drugs. Kumazoe et al (2013) also reported the synergistic effect on cancer inhibition between EGCG and anti-cancer agents. EGCG activated 67-kDa lamina receptors in multiple myeloma cells, resulting in elevated cyclic guanosinc monophosphate (cGMP) levels, which initiated apoptosis through the activation of protein kinase C-δ (PKCδ) and acid sphingomyelinase in a novel death pathway.…”