Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

Mart Bittremieux, Rita M. la Rovere, Haidar Akl, Claudio Martines, Kirsten Welkenhuyzen, Kathia Dubron, Myriam Baes, Ann Janssens, Peter Vandenberghe, Luca Laurenti, Katja Rietdorf, Giampaolo Morciano, Paolo Pinton, Katsuhiko Mikoshiba, Martin D. Bootman, Dimitar G. Efremov, Humbert de Smedt, Jan B. Parys, Geert Bultynck

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP3Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP3R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP3R2-expression levels, but also on constitutive IP3 signaling, downstream of the tonically active B-cell receptor. The basal Ca2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP3 production. This constitutive IP3 signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 µM) or expression of an IP3 sponge suppressed both BIRD-2-induced Ca2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP3R activity. BIRD-2 seems to switch constitutive IP3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - Jun 13 2018

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
Neoplasms
Type C Phospholipases
Cell Death
B-Cell Chronic Lymphocytic Leukemia
Apoptosis
Cell Line
CD40 Ligand
Inositol 1,4,5-Trisphosphate
Porifera
Coculture Techniques
Lymphoma
Cell Survival
Leukemia
Fibroblasts

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Bittremieux, M., la Rovere, R. M., Akl, H., Martines, C., Welkenhuyzen, K., Dubron, K., ... Bultynck, G. (Accepted/In press). Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2. Cell Death and Differentiation, 1-17. https://doi.org/10.1038/s41418-018-0142-3

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2. / Bittremieux, Mart; la Rovere, Rita M.; Akl, Haidar; Martines, Claudio; Welkenhuyzen, Kirsten; Dubron, Kathia; Baes, Myriam; Janssens, Ann; Vandenberghe, Peter; Laurenti, Luca; Rietdorf, Katja; Morciano, Giampaolo; Pinton, Paolo; Mikoshiba, Katsuhiko; Bootman, Martin D.; Efremov, Dimitar G.; de Smedt, Humbert; Parys, Jan B.; Bultynck, Geert.

In: Cell Death and Differentiation, 13.06.2018, p. 1-17.

Research output: Contribution to journalArticle

Bittremieux, M, la Rovere, RM, Akl, H, Martines, C, Welkenhuyzen, K, Dubron, K, Baes, M, Janssens, A, Vandenberghe, P, Laurenti, L, Rietdorf, K, Morciano, G, Pinton, P, Mikoshiba, K, Bootman, MD, Efremov, DG, de Smedt, H, Parys, JB & Bultynck, G 2018, 'Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2', Cell Death and Differentiation, pp. 1-17. https://doi.org/10.1038/s41418-018-0142-3
Bittremieux, Mart ; la Rovere, Rita M. ; Akl, Haidar ; Martines, Claudio ; Welkenhuyzen, Kirsten ; Dubron, Kathia ; Baes, Myriam ; Janssens, Ann ; Vandenberghe, Peter ; Laurenti, Luca ; Rietdorf, Katja ; Morciano, Giampaolo ; Pinton, Paolo ; Mikoshiba, Katsuhiko ; Bootman, Martin D. ; Efremov, Dimitar G. ; de Smedt, Humbert ; Parys, Jan B. ; Bultynck, Geert. / Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2. In: Cell Death and Differentiation. 2018 ; pp. 1-17.
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abstract = "Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP3Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP3R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP3R2-expression levels, but also on constitutive IP3 signaling, downstream of the tonically active B-cell receptor. The basal Ca2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP3 production. This constitutive IP3 signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 µM) or expression of an IP3 sponge suppressed both BIRD-2-induced Ca2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP3R activity. BIRD-2 seems to switch constitutive IP3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.",
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AU - Bittremieux, Mart

AU - la Rovere, Rita M.

AU - Akl, Haidar

AU - Martines, Claudio

AU - Welkenhuyzen, Kirsten

AU - Dubron, Kathia

AU - Baes, Myriam

AU - Janssens, Ann

AU - Vandenberghe, Peter

AU - Laurenti, Luca

AU - Rietdorf, Katja

AU - Morciano, Giampaolo

AU - Pinton, Paolo

AU - Mikoshiba, Katsuhiko

AU - Bootman, Martin D.

AU - Efremov, Dimitar G.

AU - de Smedt, Humbert

AU - Parys, Jan B.

AU - Bultynck, Geert

PY - 2018/6/13

Y1 - 2018/6/13

N2 - Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP3Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP3R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP3R2-expression levels, but also on constitutive IP3 signaling, downstream of the tonically active B-cell receptor. The basal Ca2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP3 production. This constitutive IP3 signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 µM) or expression of an IP3 sponge suppressed both BIRD-2-induced Ca2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP3R activity. BIRD-2 seems to switch constitutive IP3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.

AB - Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-mediated Ca2+-signaling. A peptide tool (Bcl-2/IP3R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP3Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP3R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP3R2-expression levels, but also on constitutive IP3 signaling, downstream of the tonically active B-cell receptor. The basal Ca2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP3 production. This constitutive IP3 signaling fulfilled a pro-survival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 µM) or expression of an IP3 sponge suppressed both BIRD-2-induced Ca2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP3R activity. BIRD-2 seems to switch constitutive IP3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.

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