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Bcl2L13 is a ceramide synthase inhibitor in glioblastoma
Samuel A Jensen1, Andrea E Calvert, Giora Volpert
1Ken 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.
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.
Insights
Researchers discovered Bcl2-like 13 (Bcl2L13) promotes cancer therapy resistance by inhibiting apoptosis. Targeting the Bcl2L13-ceramide synthase axis may improve cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Therapy resistance significantly hinders effective cancer treatment.
- Bcl2-like 13 (Bcl2L13) is identified as a novel factor in cancer therapy resistance.
Purpose of the Study:
- To investigate the role of Bcl2L13 in cancer therapy susceptibility.
- To elucidate the molecular mechanism by which Bcl2L13 influences apoptosis and tumor growth.
- To explore the Bcl2L13-ceramide synthase (CerS) axis as a potential therapeutic target.
Main Methods:
- Expression analysis of Bcl2L13 in various cancers, including glioblastoma (GBM).
- In vitro and in vivo experiments to assess Bcl2L13's impact on apoptosis and tumor growth.
- Co-immunoprecipitation and functional assays to determine Bcl2L13's interaction with ceramide synthases (CerS2 and CerS6).
Main Results:
- Bcl2L13 expression is elevated in solid and blood cancers, including GBM.
- Mitochondria-associated Bcl2L13 inhibits chemotherapy- and targeted therapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization.
- Bcl2L13 binds to CerS2 and CerS6, inhibiting their complex formation and activity, with an inverse correlation observed in GBM tumors.
- Bcl2L13 promotes GBM tumor growth in vivo.
Conclusions:
- Bcl2L13 acts as a regulator of therapy susceptibility by inhibiting apoptosis through interaction with CerS2/6.
- The Bcl2L13-CerS axis represents a promising therapeutic target for overcoming resistance to conventional and targeted cancer therapies.
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