cyclic-gmp and Multiple-Myeloma

Epigallocatechin-3-O-gallate (EGCG)-induced cyclic guanosine monophosphate (cGMP) plays a crucial role in EGCG-induced cell death in various types of cancer cells. However, little is known regarding the early molecular events after cGMP induction. In this study, we showed that cGMP induction is sufficient to induce the phosphorylation of protein kinase C delta (PKCδ) at Ser664, the crucial kinase for EGCG-induced activation of acid sphingomyelinase (ASM). Using a chemical inhibitor library, we revealed that the inhibitors of the negative regulators of diacylglycerol strongly increase the effect of EGCG. We also showed that EGCG treatment increased phospholipase C (PLC) activity, and the same results were obtained with cGMP inducer treatment. EGCG-induced ASM activation was completely suppressed by pharmacological inhibition of PLC. Collectively, EGCG-induced cGMP activated the cGMP/PLC/PKCδ/ASM signaling axis in multiple myeloma cells.

Topics: Apoptosis; Catechin; Cell Line, Tumor; Cyclic GMP; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Multiple Myeloma; Phosphorylation; Signal Transduction; Sphingomyelin Phosphodiesterase; Type C Phospholipases

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.

Topics: Animals; Apoptosis; Caspases; Catechin; Cell Line, Tumor; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Imidazoles; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Molecular Weight; Multiple Myeloma; Neoplasms; Phosphodiesterase 5 Inhibitors; Piperazines; Receptors, Laminin; Signal Transduction; Sulfones; Triazines; Vardenafil Dihydrochloride; Xenograft Model Antitumor Assays

Topics: Aminophylline; Animals; Binding Sites, Antibody; Butyrates; Cell Line; Cell Membrane; Cyclic AMP; Cyclic GMP; Depression, Chemical; Immune Adherence Reaction; Immunoglobulin Fc Fragments; Mice; Mice, Inbred BALB C; Multiple Myeloma; Stimulation, Chemical; Toxins, Biological; Toxoids; Vibrio cholerae

Topics: Aminophylline; Animals; Binding Sites, Antibody; Butyrates; Cell Line; Cell Membrane; Cyclic AMP; Cyclic GMP; Depression, Chemical; Immune Adherence Reaction; Immunoglobulin Fc Fragments; Mice; Mice, Inbred BALB C; Multiple Myeloma; Stimulation, Chemical; Toxins, Biological; Toxoids; Vibrio cholerae