Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Samuel A. Jensen, Andrea E. Calvert, Giora Volpert, Fotini M. Kouri, Lisa A. Hurley, Janina P. Luciano, Yongfei Wu, Alexandra Chalastanis, Anthony H. Futerman, Alexander H. Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5682-5687
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number15
DOIs
StatePublished - Apr 15 2014

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Keywords

  • Bcl-2 protein family
  • Intrinsic apoptosis signaling

ASJC Scopus subject areas

  • General

Cite this

Jensen, S. A., Calvert, A. E., Volpert, G., Kouri, F. M., Hurley, L. A., Luciano, J. P., Wu, Y., Chalastanis, A., Futerman, A. H., & Stegh, A. H. (2014). Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 111(15), 5682-5687. https://doi.org/10.1073/pnas.1316700111