title: Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene.
abstract: Because the emergence of drug resistance is a major limitation of current treatments for multiple myeloma (MM), it is necessary to continuously develop novel anticancer strategies. Here, using an inactivated Sendai virus (Hemagglutinating Virus of Japan; HVJ) envelope (HVJ-E), we discovered that increase of cytoplasmic Ca2+ by virus-cell fusion significantly induced apoptosis against human MM cells but not peripheral blood mononuclear cells from healthy donors. Interaction of F protein of HVJ-E with MM cells increased intracellular Ca2+ level of MMs by the induction of Ca2+ efflux from endoplasmic reticulum but not influx from extracellular region. The elevation of the Ca2+ cytoplasmic level induced SMAD1/5/8 phosphorylation and translocation into the nucleus, and SMAD1/5/8 and SMAD4 complex suppressed c-Myc transcription. Meanwhile, HVJ-E decreases S62 phosphorylation of c-Myc and promotes c-Myc protein degradation. Thus, HVJ-E-induced cell death of MM resulted from suppression of c-Myc by both destabilization of c-Myc protein and downregulation of c-Myc transcription. This study indicates that HVJ-E will be a promising tool for MM therapy.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Saga
authors.affiliation: Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D008561:Membrane Fusion; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D029082:Sendai virus / Q000378:metabolism* / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000378:metabolism; D038301:Virus Inactivation
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051785:Smad Proteins; D014760:Viral Fusion Proteins; D002118:Calcium
keywords: Ca2+; HVJ-E; apoptosis; c-Myc; multiple myeloma