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.
Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Samuel A
SA
Jensen
Andrea E
AE
Calvert
Giora
G
Volpert
Fotini M
FM
Kouri
Lisa A
LA
Hurley
Janina P
JP
Luciano
Yongfei
Y
Wu
Alexandra
A
Chalastanis
Anthony H
AH
Futerman
Alexander H
AH
Stegh
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003001:Cloning, Molecular; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015723:Gene Library; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D000970:Antineoplastic Agents; C431152:BCL2L13 protein, human; D017931:DNA Primers; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C438311:CERS2 protein, human; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase
Bcl-2 protein family; intrinsic apoptosis signaling