Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Samuel A. Jensen, Andrea E. Calvert, Giora Volpert, Foteini 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

39 Citations (Scopus)

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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Glioblastoma
Neoplasms
Therapeutics
bcl-2-Associated X Protein
Mitochondrial Membranes
Genetic Therapy
Mitochondria
dihydroceramide desaturase
Apoptosis
Membranes
Growth

Keywords

  • Bcl-2 protein family
  • Intrinsic apoptosis signaling

ASJC Scopus subject areas

  • General

Cite this

Jensen, Samuel A. ; Calvert, Andrea E. ; Volpert, Giora ; Kouri, Foteini ; Hurley, Lisa A. ; Luciano, Janina P. ; Wu, Yongfei ; Chalastanis, Alexandra ; Futerman, Anthony H. ; Stegh, Alexander H. / Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 15. pp. 5682-5687.
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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.",
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Jensen, SA, Calvert, AE, Volpert, G, Kouri, F, Hurley, LA, Luciano, JP, Wu, Y, Chalastanis, A, Futerman, AH & Stegh, AH 2014, 'Bcl2L13 is a ceramide synthase inhibitor in glioblastoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 15, pp. 5682-5687. https://doi.org/10.1073/pnas.1316700111

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. / Jensen, Samuel A.; Calvert, Andrea E.; Volpert, Giora; Kouri, Foteini; Hurley, Lisa A.; Luciano, Janina P.; Wu, Yongfei; Chalastanis, Alexandra; Futerman, Anthony H.; Stegh, Alexander H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 15, 15.04.2014, p. 5682-5687.

Research output: Contribution to journalArticle

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T1 - Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

AU - Jensen, Samuel A.

AU - Calvert, Andrea E.

AU - Volpert, Giora

AU - Kouri, Foteini

AU - Hurley, Lisa A.

AU - Luciano, Janina P.

AU - Wu, Yongfei

AU - Chalastanis, Alexandra

AU - Futerman, Anthony H.

AU - Stegh, Alexander H

PY - 2014/4/15

Y1 - 2014/4/15

N2 - 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.

AB - 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.

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KW - Intrinsic apoptosis signaling

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