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

被引:65
作者
Bittremieux, Mart [1 ,2 ]
La Rovere, Rita M. [1 ,2 ]
Akl, Haidar [1 ,2 ,14 ]
Martines, Claudio [3 ]
Welkenhuyzen, Kirsten [1 ,2 ]
Dubron, Kathia [1 ,2 ]
Baes, Myriam [4 ]
Janssens, Ann [5 ]
Vandenberghe, Peter [5 ,6 ]
Laurenti, Luca [7 ]
Rietdorf, Katja [8 ]
Morciano, Giampaolo [9 ,10 ,11 ,12 ]
Pinton, Paolo [9 ,10 ,12 ]
Mikoshiba, Katsuhiko [13 ]
Bootman, Martin D. [8 ]
Efremov, Dimitar G. [3 ]
De Smedt, Humbert [1 ,2 ]
Parys, Jan B. [1 ,2 ]
Bultynck, Geert [1 ,2 ]
机构
[1] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Mol & Cellular Signaling, Leuven, Belgium
[2] Katholieke Univ Leuven, Leuven Kanker Inst, Leuven, Belgium
[3] ICGEB, Mol Hematol Unit, Trieste, Italy
[4] Katholieke Univ Leuven, Cell Metab, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium
[5] UZ Leuven, Dept Hematol, Leuven, Belgium
[6] Katholieke Univ Leuven, Dept Human Genet, Leuven, Belgium
[7] Univ Cattolica Sacro Cuore, Fdn Policlin A Gemelli, Rome, Italy
[8] Open Univ, Sch Life Hlth & Chem Sci, Milton Keynes, Bucks, England
[9] Univ Ferrara, Dept Morphol Surg & Expt Med, Sect Pathol Oncol & Expt Biol, Ferrara, Italy
[10] Univ Ferrara, LTTA Ctr, Ferrara, Italy
[11] Maria Pia Hosp, GVM Care & Res, Turin, Italy
[12] Maria Cecilia Hosp, GVM Care & Res, Cotignola, Italy
[13] RIKEN, Brain Sci Inst, Lab Dev Neurobiol, Wako, Saitama, Japan
[14] Lebanese Univ, Dept Biol, Hadath, Lebanon
关键词
INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; BH4; DOMAIN; ENDOPLASMIC-RETICULUM; CALCIUM-RELEASE; APOPTOSIS; ER; MITOCHONDRIAL; INHIBITION; PTEN;
D O I
10.1038/s41418-018-0142-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 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 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 mu M) caused cell death in SU-DHL-4 cells. Milder inhibition of IP3 signaling using a lower U73122 concentration (1 mu M) 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.
引用
收藏
页码:531 / 547
页数:17
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