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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 15 Pg. 5682-7 (Apr 15 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24706805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BCL2L13 protein, human
• DNA Primers
• Membrane Proteins
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Proteins
• Oxidoreductases
• dihydroceramide desaturase
• CERS2 protein, human
• CERS6 protein, human
• Sphingosine N-Acyltransferase

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cloning, Molecular
• Computational Biology
• DNA Primers (genetics)
• Drug Resistance (genetics)
• Gene Expression Regulation, Enzymologic (physiology)
• Gene Library
• Glioblastoma (drug therapy, enzymology)
• Humans
• Membrane Proteins (metabolism)
• Oxidoreductases (antagonists & inhibitors)
• Polymerase Chain Reaction
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Saccharomyces cerevisiae
• Sphingosine N-Acyltransferase (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Two-Hybrid System Techniques