Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance
Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance
ABSTRACT Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptotic programs. We isolated mitochondria from neuroblastoma cell lines obtained from children at diagnosis and after relapse following failed therapy, and profiled responses to tBid and Bim, death effectors activated by therapeutic stress. Mitochondria from post-relapse models had markedly attenuated cytochrome c release (surrogate for apoptotic commitment) in comparison with patient-matched diagnostic models. Mitochondrial DNA content, size, and shape did not differ consistently. However, we used electron microscopy to identify reduced endoplasmic reticulum-mitochondria contacts (ERMCs) as correlated with therapy resistance. ERMCs form microdomains for the transfer of Ca2+ to mitochondria. We confirmed reduced Ca2+ transfer in resistant cells, with restoration by re-opposing ERMCs via genetically-encoded linkers. However, reduced Ca2+ transfer was not present in all ERMC-reduced cancers with therapy resistance, supporting Ca2+-independent mechanisms. Genetically or biochemically reducing ERMCs in therapy sensitive tumors phenocopied resistance, validating these inter-organelle contacts as physiologic regulators of apoptosis. Our work confirms the importance of ERMCs in stress signaling and provides a previously unrecognized mechanism for cancer cell resistance that is not exclusive to other contributors.
Booth David M.、Coku Jorida、Pedrotty Madison C.、Vogel Jennifer、Liu Kangning、Carpenter Erica L.、Ye Jamie C.、Chen Michelle A.、Scadden Elizabeth、Patrick Reynolds C.、Hajnoczky Gyorgy、Hogarty Michael D.、Li Yimei、Goldsmith Kelly C.、Vu Annette、Nakamaru-Ogiso Eiko、Skoda Jan、Dunbar Peter
MitoCare Center, Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson UniversityCancer Biology Program, Perelman School of Medicine at the University of PennsylvaniaDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaDepartment of Radiation Oncology, Perelman School of Medicine at the University of PennsylvaniaDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaDepartment of Medicine, Perelman School of Medicine at the University of PennsylvaniaDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaTTUHSC Cancer Center, Texas Tech University Health Sciences CenterMitoCare Center, Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson UniversityDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of Philadelphia||Department of Pediatrics, Perelman School of Medicine at the University of PennsylvaniaDepartment of Biostatistics, Perelman School of Medicine at the University of PennsylvaniaDepartment of Pediatrics, Emory University School of MedicineDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of PhiladelphiaMitochondrial Medicine Frontier Program, Division of Human Genetics, The Children?ˉs Hospital of Philadelphia||Department of Pediatrics, Perelman School of Medicine at the University of PennsylvaniaDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityDivision of Oncology and Center for Childhood Cancer Research, The Children?ˉs Hospital of Philadelphia
肿瘤学基础医学分子生物学
inter-organelle contactsdrug resistancemitochondria-associated membranescalcium signalsneuroblastoma
Booth David M.,Coku Jorida,Pedrotty Madison C.,Vogel Jennifer,Liu Kangning,Carpenter Erica L.,Ye Jamie C.,Chen Michelle A.,Scadden Elizabeth,Patrick Reynolds C.,Hajnoczky Gyorgy,Hogarty Michael D.,Li Yimei,Goldsmith Kelly C.,Vu Annette,Nakamaru-Ogiso Eiko,Skoda Jan,Dunbar Peter.Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2021.03.01.433120.点此复制
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