| COKU, Jorida, David M BOOTH, Jan ŠKODA, Madison C PEDROTTY, Jennifer VOGEL, Kangning LIU, Annette VU, Erica L CARPENTER, Jamie C YE, Michelle A CHEN, Peter DUNBAR, Elizabeth SCADDEN, Taekyung D YUN, Eiko NAKAMARU-OGISO, Estela AREA-GOMEZ, Yimei LI, Kelly C GOLDSMITH, C Patrick REYNOLDS, Gyorgy HAJNOCZKY and Michael D HOGARTY. Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance. EMBO Journal. Hoboken: Wiley, 2022, vol. 41, No 8, p. 1-20. ISSN 0261-4189. Available from: https://dx.doi.org/10.15252/embj.2021108272. |
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@article{1842138,
author = {Coku, Jorida and Booth, David M and Škoda, Jan and Pedrotty, Madison C and Vogel, Jennifer and Liu, Kangning and Vu, Annette and Carpenter, Erica L and Ye, Jamie C and Chen, Michelle A and Dunbar, Peter and Scadden, Elizabeth and Yun, Taekyung D and NakamaruandOgiso, Eiko and AreaandGomez, Estela and Li, Yimei and Goldsmith, Kelly C and Reynolds, C Patrick and Hajnoczky, Gyorgy and Hogarty, Michael D},
article_location = {Hoboken},
article_number = {8},
doi = {http://dx.doi.org/10.15252/embj.2021108272},
keywords = {ceramides; inter-organelle contacts; mitochondria-associated membranes; multidrug resistance; sphingolipids},
language = {eng},
issn = {0261-4189},
journal = {EMBO Journal},
title = {Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance},
url = {https://www.embopress.org/doi/full/10.15252/embj.2021108272},
volume = {41},
year = {2022}
}
TY - JOUR
ID - 1842138
AU - Coku, Jorida - Booth, David M - Škoda, Jan - Pedrotty, Madison C - Vogel, Jennifer - Liu, Kangning - Vu, Annette - Carpenter, Erica L - Ye, Jamie C - Chen, Michelle A - Dunbar, Peter - Scadden, Elizabeth - Yun, Taekyung D - Nakamaru-Ogiso, Eiko - Area-Gomez, Estela - Li, Yimei - Goldsmith, Kelly C - Reynolds, C Patrick - Hajnoczky, Gyorgy - Hogarty, Michael D
PY - 2022
TI - Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance
JF - EMBO Journal
VL - 41
IS - 8
SP - 1-20
EP - 1-20
PB - Wiley
SN - 02614189
KW - ceramides
KW - inter-organelle contacts
KW - mitochondria-associated membranes
KW - multidrug resistance
KW - sphingolipids
UR - https://www.embopress.org/doi/full/10.15252/embj.2021108272
N2 - 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 apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.
ER -
COKU, Jorida, David M BOOTH, Jan ŠKODA, Madison C PEDROTTY, Jennifer VOGEL, Kangning LIU, Annette VU, Erica L CARPENTER, Jamie C YE, Michelle A CHEN, Peter DUNBAR, Elizabeth SCADDEN, Taekyung D YUN, Eiko NAKAMARU-OGISO, Estela AREA-GOMEZ, Yimei LI, Kelly C GOLDSMITH, C Patrick REYNOLDS, Gyorgy HAJNOCZKY and Michael D HOGARTY. Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance. \textit{EMBO Journal}. Hoboken: Wiley, 2022, vol.~41, No~8, p.~1-20. ISSN~0261-4189. Available from: https://dx.doi.org/10.15252/embj.2021108272.
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