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Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.

ABSTRACT: Therapy resistance is a major limitation to the successful treatment of cancer. Here, we identify Bcl2-like 13 (Bcl2L13), an atypical member of the Bcl-2 family, as a therapy susceptibility gene with elevated expression in solid and blood cancers, including glioblastoma (GBM). We demonstrate that mitochondria-associated Bcl2L13 inhibits apoptosis induced by a wide spectrum of chemo- and targeted therapies upstream of Bcl2-associated X protein activation and mitochondrial outer membrane permeabilization in vitro and promotes GBM tumor growth in vivo. Mechanistically, Bcl2L13 binds to proapoptotic ceramide synthases 2 (CerS2) and 6 (CerS6) via a unique C-terminal 250-aa sequence located between its Bcl-2 homology and membrane anchor domains and blocks homo- and heteromeric CerS2/6 complex formation and activity. Correspondingly, CerS2/6 activity and Bcl2L13 abundance are inversely correlated in GBM tumors. Thus, our genetic and functional studies identify Bcl2L13 as a regulator of therapy susceptibility and point to the Bcl2L13-CerS axis as a promising target to enhance responses of therapy-refractory cancers toward conventional and targeted regimens currently in clinical use.

SUBMITTER: Jensen SA

PROVIDER: S-EPMC3992626 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.

Jensen Samuel A SA Calvert Andrea E AE Volpert Giora G Kouri Fotini M FM Hurley Lisa A LA Luciano Janina P JP Wu Yongfei Y Chalastanis Alexandra A Futerman Anthony H AH Stegh Alexander H AH

Proceedings of the National Academy of Sciences of the United States of America 20140331 15

Therapy resistance is a major limitation to the successful treatment of cancer. Here, we identify Bcl2-like 13 (Bcl2L13), an atypical member of the Bcl-2 family, as a therapy susceptibility gene with elevated expression in solid and blood cancers, including glioblastoma (GBM). We demonstrate that mitochondria-associated Bcl2L13 inhibits apoptosis induced by a wide spectrum of chemo- and targeted therapies upstream of Bcl2-associated X protein activation and mitochondrial outer membrane permeabil ...[more]

PMID: 24706805

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Project description:Fumonisin (FB) mycotoxins produced by species of the genus Fusarium detrimentally affect human and animal health upon consumption, due to the inhibition of ceramide synthase. In the present work, we set out to identify mechanisms of self-protection employed by the FB1 producer Fusarium verticillioides FB1 biosynthesis was shown to be compartmentalized, and two cluster-encoded self-protection mechanisms were identified. First, the ATP-binding cassette transporter Fum19 acts as a repressor of the FUM gene cluster. Appropriately, FUM19 deletion and overexpression increased and decreased, respectively, the levels of intracellular and secreted FB1 Second, the cluster genes FUM17 and FUM18 were shown to be two of five ceramide synthase homologs in Fusarium verticillioides, grouping into the two clades CS-I and CS-II in a phylogenetic analysis. The ability of FUM18 to fully complement the yeast ceramide synthase null mutant LAG1/LAC1 demonstrated its functionality, while coexpression of FUM17 and CER3 partially complemented, likely via heterodimer formation. Cell viability assays revealed that Fum18 contributes to the fungal self-protection against FB1 and increases resistance by providing FUM cluster-encoded ceramide synthase activity.IMPORTANCE The biosynthesis of fungal natural products is highly regulated not only in terms of transcription and translation but also regarding the cellular localization of the biosynthetic pathway. In all eukaryotes, the endoplasmic reticulum (ER) is involved in the production of organelles, which are subject to cellular traffic or secretion. Here, we show that in Fusarium verticillioides, early steps in fumonisin production take place in the ER, together with ceramide biosynthesis, which is targeted by the mycotoxin. A first level of self-protection is given by the presence of a FUM cluster-encoded ceramide synthase, Fum18, hitherto uncharacterized. In addition, the final fumonisin biosynthetic step occurs in the cytosol and is thereby spatially separate from the fungal ceramide synthases. We suggest that these strategies help the fungus to avoid self-poisoning during mycotoxin production.

Dataset Information

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.

Publications

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.

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