Reduced ER–mitochondria connectivity promotes neuroblastoma multidrug resistance

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Authors

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

Year of publication 2022
Type Article in Periodical
Magazine / Source EMBO Journal
MU Faculty or unit

Faculty of Science

Citation
Web https://www.embopress.org/doi/full/10.15252/embj.2021108272
Doi http://dx.doi.org/10.15252/embj.2021108272
Keywords ceramides; inter-organelle contacts; mitochondria-associated membranes; multidrug resistance; sphingolipids
Description 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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