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

Akl, Haidar; Rovere, Rita M. La; Janssens, Ann; Vandenberghe, Peter; Parys, Jan B.; Bultynck, Geert

doi:10.1387/ijdb.150213gb

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…BIRD-2 disrupts endogenous Bcl-2/IP 3 R complexes, thereby triggering Ca 2+ -driven apoptosis in different malignancies, including CLL [18,20,30], DLBCL [20], multiple myeloma [31], follicular lymphoma [31], and small cell lung cell carcinoma [32]. DLBCL cells displayed a varying sensitivity to BIRD-2, which correlated to the expression levels of IP 3 R2 [20].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Dysregulated expression of Bcl-2 has been described in various cancers, such as chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DL-BCL), non-small cell lung carcinoma, multiple myeloma, follicular lymphoma and small cell lung cancer (Packham, 1998). BIRD2, a Bcl-2/IP3R inhibitor, has shown promising results in the treatment of B-cell cancers (Akl et al, 2015), small cell lung cancer, CLL, multiple myeloma and follicular lymphoma , Lavik et al, 2015. Bcl-XL is another oncogene belonging to the Bcl-2 family that is frequently overexpressed in tumors.…”

Section: Cancermentioning

confidence: 99%

The role of mitochondria-associated membranes in cellular homeostasis and diseases

Perrone

Caroccia

Genovese

et al. 2020

International Review of Cell and Molecular Biology

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Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (Mitochondria-Associated Membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals.In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. Infact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.MFN2 defining it as a ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication (Naon et al., 2016). This topic is still controversial with opposite results (Filadi et al., 2017) which allow for further considerations about MFN2 functions. Another protein complex whose function is to modulate ER-mitochondria juxtaposition is the complex formed by inositol 1,4,5-trisphosphate receptors (IP3Rs), the voltage-dependent anion channel (VDAC) and the OMM chaperone Grp75 as described in Figure 1 (Szabadkai et al., 2006). This interaction is considered functional because it promotes the efficient transfer of calcium from the ER to mitochondria. In fact, silencing of Grp75 in HeLa cells abolished Ca 2+ accumulation in mitochondria, highlighting chaperone-mediated conformational coupling between the IP3R and mitochondrial machinery. Nevertheless, a recent study of Bartok et al. reveals a non-canonical and structural role for the IP3Rs independently from calcium flux (Bartok et al., 2019).They display that IP3Rs are required for maintaining ER-mitochondrial contacts. Recently, a study of the Transglutaminase type 2 (TG2) interactome showed an enzymatic interaction with GRP75 in the MAM fraction (D'Eletto et al., 2018). In fact, silencing of the TG2-GRP75 complex leads to an increase in the interaction between IP3R-3 and GRP75, a reduction in the number of ER-mitochondria contact sites, impairment of ER-mitochondrial Ca 2+ flux and an altered MAM proteome profile. Furthermore, the complex formed between ER vesicle-associated membrane protein-associated protein B (VAPB) and PTPIP51 regulates the modulation of Ca 2+ homeostasis by MAMs (De Vos et al., 2012).

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“…Currently, the most promising peptide allowing for IP3R modulation through Bcl-2 is the Bcl-2-IP3R disrupter-2 (BIRD-2). As a BH4 mimetic, BIRD-2 targets the BH4 domain of Bcl-2, preventing its interaction with IP3R and inducing apoptosis through IP3R signaling [121,122]. Interestingly, a recent study showed that both ER and extracellular calcium content are crucial to determine the efficiency of BIRD-2, as it is able to switch IP3R signaling from pro-survival to pro-apoptotic [123].…”

Section: Inositol 145-trisphosphate Receptor (Ip3r)mentioning

confidence: 99%

Partners in Crime: Towards New Ways of Targeting Calcium Channels

Noyer

Lemonnier

Mariot

et al. 2019

IJMS

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The characterization of calcium channel interactome in the last decades opened a new way of perceiving ion channel function and regulation. Partner proteins of ion channels can now be considered as major components of the calcium homeostatic mechanisms, while the reinforcement or disruption of their interaction with the channel units now represents an attractive target in research and therapeutics. In this review we will focus on the targeting of calcium channel partner proteins in order to act on the channel activity, and on its consequences for cell and organism physiology. Given the recent advances in the partner proteins’ identification, characterization, as well as in the resolution of their interaction domain structures, we will develop the latest findings on the interacting proteins of the following channels: voltage-dependent calcium channels, transient receptor potential and ORAI channels, and inositol 1,4,5-trisphosphate receptor.

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

Cited by 21 publications

References 34 publications

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

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

The role of mitochondria-associated membranes in cellular homeostasis and diseases

Partners in Crime: Towards New Ways of Targeting Calcium Channels

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