Dataset Information

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

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.

SUBMITTER: Bittremieux M

PROVIDER: S-EPMC6370760 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Bittremieux Mart M La Rovere Rita M RM Akl Haidar H Martines Claudio C Welkenhuyzen Kirsten K Dubron Kathia K Baes Myriam M Janssens Ann A Vandenberghe Peter P Laurenti Luca L Rietdorf Katja K Morciano Giampaolo G Pinton Paolo P Mikoshiba Katsuhiko K Bootman Martin D MD Efremov Dimitar G DG De Smedt Humbert H Parys Jan B JB Bultynck Geert G

Cell death and differentiation 20180613 3

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. ...[more]

PMID: 29899382

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Project description:In the human-pathogenic fungus Cryptococcus neoformans, the inositol polyphosphate signaling pathway is critical for virulence. We recently demonstrated the key role of the inositol pyrophosphate IP7 (isomer 5-PP-IP5) in driving fungal virulence; however, the mechanism of action remains elusive. Using genetic and biochemical approaches, and mouse infection models, we show that IP7 synthesized by Kcs1 regulates fungal virulence by binding to a conserved lysine surface cluster in the SPX domain of Pho81. Pho81 is the cyclin-dependent kinase (CDK) inhibitor of the phosphate signaling (PHO) pathway. We also provide novel mechanistic insight into the role of IP7 in PHO pathway regulation by demonstrating that IP7 functions as an intermolecular "glue" to stabilize Pho81 association with Pho85/Pho80 and, hence, promote PHO pathway activation and phosphate acquisition. Blocking IP7-Pho81 interaction using site-directed mutagenesis led to a dramatic loss of fungal virulence in a mouse infection model, and the effect was similar to that observed following PHO81 gene deletion, highlighting the key importance of Pho81 in fungal virulence. Furthermore, our findings provide additional evidence of evolutionary divergence in PHO pathway regulation in fungi by demonstrating that IP7 isomers have evolved different roles in PHO pathway control in C. neoformans and nonpathogenic yeast.IMPORTANCE Invasive fungal diseases pose a serious threat to human health globally with >1.5 million deaths occurring annually, 180,000 of which are attributable to the AIDS-related pathogen, Cryptococcus neoformans Here, we demonstrate that interaction of the inositol pyrophosphate, IP7, with the CDK inhibitor protein, Pho81, is instrumental in promoting fungal virulence. IP7-Pho81 interaction stabilizes Pho81 association with other CDK complex components to promote PHO pathway activation and phosphate acquisition. Our data demonstrating that blocking IP7-Pho81 interaction or preventing Pho81 production leads to a dramatic loss in fungal virulence, coupled with Pho81 having no homologue in humans, highlights Pho81 function as a potential target for the development of urgently needed antifungal drugs.

Dataset Information

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

Publications

Constitutive IP<sub>3</sub> signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP<sub>3</sub> receptor disruptor BIRD-2.

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