Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance

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Publikace nespadá pod Filozofickou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.
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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

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj EMBO Journal
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://www.embopress.org/doi/full/10.15252/embj.2021108272
Doi http://dx.doi.org/10.15252/embj.2021108272
Klíčová slova ceramides; inter-organelle contacts; mitochondria-associated membranes; multidrug resistance; sphingolipids
Popis 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.
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