Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.

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.
Mesh Terms:
Antineoplastic Agents, Apoptosis, Blotting, Western, Cloning, Molecular, Computational Biology, DNA Primers, Drug Resistance, Gene Expression Regulation, Enzymologic, Gene Library, Glioblastoma, Humans, Membrane Proteins, Oxidoreductases, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcl-2, Saccharomyces cerevisiae, Sphingosine N-Acyltransferase, Tumor Suppressor Proteins, Two-Hybrid System Techniques
Proc Natl Acad Sci U S A
Date: Apr. 15, 2014
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