Constitutive IP 3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP 3 receptor disruptor BIRD-2
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 ) receptor (IP R)-mediated Ca -signaling...
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| Veröffentlicht in: | Cell death and differentiation 2019-03, Vol.26 (3), p.531 |
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| creator | 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 |
| description | 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
) receptor (IP
R)-mediated Ca
-signaling. A peptide tool (Bcl-2/IP
R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP
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
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
R2-expression levels, but also on constitutive IP
signaling, downstream of the tonically active B-cell receptor. The basal Ca
level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP
production. This constitutive IP
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 IP
signaling using a lower U73122 concentration (1 µM) or expression of an IP
sponge suppressed both BIRD-2-induced Ca
elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP
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
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
R activity. BIRD-2 seems to switch constitutive IP
signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy. |
| doi_str_mv | 10.1038/s41418-018-0142-3 |
| format | Article |
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) receptor (IP
R)-mediated Ca
-signaling. A peptide tool (Bcl-2/IP
R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP
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
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
R2-expression levels, but also on constitutive IP
signaling, downstream of the tonically active B-cell receptor. The basal Ca
level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP
production. This constitutive IP
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 IP
signaling using a lower U73122 concentration (1 µM) or expression of an IP
sponge suppressed both BIRD-2-induced Ca
elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP
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
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
R activity. BIRD-2 seems to switch constitutive IP
signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.</description><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-018-0142-3</identifier><identifier>PMID: 29899382</identifier><language>eng</language><publisher>England</publisher><ispartof>Cell death and differentiation, 2019-03, Vol.26 (3), p.531</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0001-7108-6508 ; 0000-0002-5968-4828 ; 0000-0002-6447-3451 ; 0000-0002-3591-4967</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29899382$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bittremieux, Mart</creatorcontrib><creatorcontrib>La Rovere, Rita M</creatorcontrib><creatorcontrib>Akl, Haidar</creatorcontrib><creatorcontrib>Martines, Claudio</creatorcontrib><creatorcontrib>Welkenhuyzen, Kirsten</creatorcontrib><creatorcontrib>Dubron, Kathia</creatorcontrib><creatorcontrib>Baes, Myriam</creatorcontrib><creatorcontrib>Janssens, Ann</creatorcontrib><creatorcontrib>Vandenberghe, Peter</creatorcontrib><creatorcontrib>Laurenti, Luca</creatorcontrib><creatorcontrib>Rietdorf, Katja</creatorcontrib><creatorcontrib>Morciano, Giampaolo</creatorcontrib><creatorcontrib>Pinton, Paolo</creatorcontrib><creatorcontrib>Mikoshiba, Katsuhiko</creatorcontrib><creatorcontrib>Bootman, Martin D</creatorcontrib><creatorcontrib>Efremov, Dimitar G</creatorcontrib><creatorcontrib>De Smedt, Humbert</creatorcontrib><creatorcontrib>Parys, Jan B</creatorcontrib><creatorcontrib>Bultynck, Geert</creatorcontrib><title>Constitutive IP 3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP 3 receptor disruptor BIRD-2</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><description>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
) receptor (IP
R)-mediated Ca
-signaling. A peptide tool (Bcl-2/IP
R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP
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
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
R2-expression levels, but also on constitutive IP
signaling, downstream of the tonically active B-cell receptor. The basal Ca
level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP
production. This constitutive IP
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 IP
signaling using a lower U73122 concentration (1 µM) or expression of an IP
sponge suppressed both BIRD-2-induced Ca
elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP
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
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
R activity. BIRD-2 seems to switch constitutive IP
signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.</description><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNo1j9tKAzEYhIMgtlYfwBvJC8T-OXSTXNp6KhQU6X3JZv-tke3ukmQF395l1Yth5uJjmCHkhsMdB2mWSXHFDYNJSjB5RuZc6YKtFMgZuUzpEwAKbYsLMhPWWCuNmJO06dqUQx5y-EK6faOSpnBsXRPaIx3aCmMTMNH8gTRhm8KIhfxNu5qumcemod61HuNIdBO09g0Ty6knosc-d5FWIcVhSuvt-wMTV-S8dk3C6z9fkP3T437zwnavz9vN_Y71VmbmQMoCHFrNy9W4VVe69DXXqva1RbDGGK-9d06NT6DidakqUQiJKECD53JBbn9r-6E8YXXoYzi5-H34Py9_ACMMWhM</recordid><startdate>201903</startdate><enddate>201903</enddate><creator>Bittremieux, Mart</creator><creator>La Rovere, Rita M</creator><creator>Akl, Haidar</creator><creator>Martines, Claudio</creator><creator>Welkenhuyzen, Kirsten</creator><creator>Dubron, Kathia</creator><creator>Baes, Myriam</creator><creator>Janssens, Ann</creator><creator>Vandenberghe, Peter</creator><creator>Laurenti, Luca</creator><creator>Rietdorf, Katja</creator><creator>Morciano, Giampaolo</creator><creator>Pinton, Paolo</creator><creator>Mikoshiba, Katsuhiko</creator><creator>Bootman, Martin D</creator><creator>Efremov, Dimitar G</creator><creator>De Smedt, Humbert</creator><creator>Parys, Jan B</creator><creator>Bultynck, Geert</creator><scope>NPM</scope><orcidid>https://orcid.org/0000-0001-7108-6508</orcidid><orcidid>https://orcid.org/0000-0002-5968-4828</orcidid><orcidid>https://orcid.org/0000-0002-6447-3451</orcidid><orcidid>https://orcid.org/0000-0002-3591-4967</orcidid></search><sort><creationdate>201903</creationdate><title>Constitutive IP 3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP 3 receptor disruptor BIRD-2</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p93t-a03360ae971b53827d7bcf174fcf9e09888c7ccaa49380d1fb4d2623ee2070c13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bittremieux, Mart</creatorcontrib><creatorcontrib>La Rovere, Rita M</creatorcontrib><creatorcontrib>Akl, Haidar</creatorcontrib><creatorcontrib>Martines, Claudio</creatorcontrib><creatorcontrib>Welkenhuyzen, Kirsten</creatorcontrib><creatorcontrib>Dubron, Kathia</creatorcontrib><creatorcontrib>Baes, Myriam</creatorcontrib><creatorcontrib>Janssens, Ann</creatorcontrib><creatorcontrib>Vandenberghe, Peter</creatorcontrib><creatorcontrib>Laurenti, Luca</creatorcontrib><creatorcontrib>Rietdorf, Katja</creatorcontrib><creatorcontrib>Morciano, Giampaolo</creatorcontrib><creatorcontrib>Pinton, Paolo</creatorcontrib><creatorcontrib>Mikoshiba, Katsuhiko</creatorcontrib><creatorcontrib>Bootman, Martin D</creatorcontrib><creatorcontrib>Efremov, Dimitar G</creatorcontrib><creatorcontrib>De Smedt, Humbert</creatorcontrib><creatorcontrib>Parys, Jan B</creatorcontrib><creatorcontrib>Bultynck, Geert</creatorcontrib><collection>PubMed</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bittremieux, Mart</au><au>La Rovere, Rita M</au><au>Akl, Haidar</au><au>Martines, Claudio</au><au>Welkenhuyzen, Kirsten</au><au>Dubron, Kathia</au><au>Baes, Myriam</au><au>Janssens, Ann</au><au>Vandenberghe, Peter</au><au>Laurenti, Luca</au><au>Rietdorf, Katja</au><au>Morciano, Giampaolo</au><au>Pinton, Paolo</au><au>Mikoshiba, Katsuhiko</au><au>Bootman, Martin D</au><au>Efremov, Dimitar G</au><au>De Smedt, Humbert</au><au>Parys, Jan B</au><au>Bultynck, Geert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Constitutive IP 3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP 3 receptor disruptor BIRD-2</atitle><jtitle>Cell death and differentiation</jtitle><addtitle>Cell Death Differ</addtitle><date>2019-03</date><risdate>2019</risdate><volume>26</volume><issue>3</issue><spage>531</spage><pages>531-</pages><eissn>1476-5403</eissn><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 (IP
) receptor (IP
R)-mediated Ca
-signaling. A peptide tool (Bcl-2/IP
R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP
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
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
R2-expression levels, but also on constitutive IP
signaling, downstream of the tonically active B-cell receptor. The basal Ca
level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP
production. This constitutive IP
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 IP
signaling using a lower U73122 concentration (1 µM) or expression of an IP
sponge suppressed both BIRD-2-induced Ca
elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP
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
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
R activity. BIRD-2 seems to switch constitutive IP
signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.</abstract><cop>England</cop><pmid>29899382</pmid><doi>10.1038/s41418-018-0142-3</doi><orcidid>https://orcid.org/0000-0001-7108-6508</orcidid><orcidid>https://orcid.org/0000-0002-5968-4828</orcidid><orcidid>https://orcid.org/0000-0002-6447-3451</orcidid><orcidid>https://orcid.org/0000-0002-3591-4967</orcidid></addata></record> |
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| ispartof | Cell death and differentiation, 2019-03, Vol.26 (3), p.531 |
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| language | eng |
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| source | SpringerLink Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| title | Constitutive IP 3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP 3 receptor disruptor BIRD-2 |
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