Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival

Ivanova, Hristina; Vervliet, Tim; Missiaen, Ludwig; Parys, Jan B.; Smedt, Humbert De; Bultynck, Geert

doi:10.1016/j.bbamcr.2014.03.007

Cited by 154 publications

(138 citation statements)

References 362 publications

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“…ITPR1 has been shown to be involved in the control of intracellular calcium signaling and the regulation of autophagy. 7 Ca 2C accumulation was, however, found to be unchanged in 786-0 cells regardless of ITPR1 expression, ruling out a role for ITPR1 in global calcium accumulation in response to NK effectors. To check whether autophagy was involved in the acquisition of resistance to NK by 786-0 cells, we initially examined the effect of autophagy modulators including serum starvation and hydroxychloroquine on 786-0 cells transfected (or not) with anti-HIF-2a or anti-ITPR1 siRNAs.…”

Section: Itpr1 a Novel Target Of Hif-2a Protects Rcc Cells From Nk-mentioning

confidence: 78%

HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

et al. 2015

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We recently investigated the role of von Hippel-Lindau (VHL) mutation and the subsequent induction of hypoxiainducible factor 2a (HIF-2a) in the regulation of renal cell carcinoma (RCC) susceptibility to natural killer (NK) cellmediated killing. We demonstrated that the resistance of VHL-mutated RCC cell line 786-0 to NK-mediated lysis requires HIF-2a and ITPR1, a direct novel target of HIF-2a, through the activation of autophagy in target cells by NK-derived signals.

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Section: Itpr1 a Novel Target Of Hif-2a Protects Rcc Cells From Nk-mentioning

confidence: 78%

HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

et al. 2015

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“…Via western-blot analysis, we measured the expression levels of IP 3 R2 and Bcl-2 in microsomes prepared from primary hepatocytes, which have a high IP 3 R2 density [26][27][28], in human liver carcinoma HepG2 cells and in the BIRD-2-sensitive (SU-DHL-4) and BIRD-2-resistant (OCI-LY-1) DLBCL cell lines (Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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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 (IP 3 ) receptor (IP 3 R)-mediated Ca 2+ -signaling. A peptide tool (Bcl-2/IP 3 R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP 3 Rs 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 IP 3 R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP 3 R2-expression levels, but also on constitutive IP 3 signaling, downstream of the tonically active B-cell receptor. The basal Ca 2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP 3 production. This constitutive IP 3 signaling fulfilled a prosurvival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP 3 signaling using a lower U73122 concentration (1 µM) or expression of an IP 3 sponge suppressed both BIRD-2-induced Ca 2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP 3 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 IP 3 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 IP 3 R activity. BIRD-2 seems to switch constitutive IP 3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.

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“…In DLBCL, a heterogeneous response to BIRD-2 has been observed. The sensitivity of DLBCL to BIRD-2 could be linked to the expression level of the IP 3 R2, the IP 3 R isoform with the highest sensitivity to IP 3 (Akl et al, 2013a;Ivanova et al, 2014;Vervloessem et al, 2015). Given the important role of Ca 2+ signaling in BIRD-2-induced cell death, we opted to study whether this could be enhanced by a Bcl-2-inhibiting tool that also impacts Ca 2+ signaling by partially inhibiting SERCA Ca 2+ -pump activity, i.e.…”

Section: While This Peptide By Itself Is Not Cytotoxic In Non-maligmentioning

confidence: 99%

HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

Akl

Rovere²,

Janssens³

et al. 2015

Int. J. Dev. Biol.

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Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival

Cited by 154 publications

References 362 publications

HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

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

HA14-1 potentiates apoptosis in B-cell cancer cells sensitive to a peptide disrupting IP3 receptor / Bcl-2 complexes

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