IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2.
IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2.
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DOI：
10.1038/cddis.2013.140
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发表时间：
2013-05-16
影响因子：
9
通讯作者：
Bultynck G
中科院分区：
文献类型：
--
作者：
Akl H;Monaco G;La Rovere R;Welkenhuyzen K;Kiviluoto S;Vervliet T;Molgó J;Distelhorst CW;Missiaen L;Mikoshiba K;Parys JB;De Smedt H;Bultynck G
使用选择性靶向Bcl-2的BH 4结构域而不是B细胞淋巴瘤2-特大型（Bcl-Xl）的BH 4结构域的细胞渗透性肽（稳定的TAT融合的IP 3R衍生肽（TAT-IDPS））破坏肌醇1，4，5-三磷酸（IP 3）受体（IP 3R）/B细胞淋巴瘤2（Bcl-2）复合物增强了慢性淋巴细胞白血病细胞中的促凋亡Ca 2+信号传导。然而，使癌细胞而不是正常细胞对破坏IP 3R/Bcl-2复合物特别敏感的分子机制知之甚少。因此，我们研究了TAT-IDPS在更异质的Bcl-2依赖性癌症模型中的作用，该模型使用一组含有升高的Bcl-2水平的“致死”弥漫性大B细胞淋巴瘤（DL-BCL）细胞系。我们发现这些细胞对TAT-IDPS的凋亡反应具有很大的异质性，SU-DHL-4最敏感，OCI-LY-1最耐药。这种敏感性与TAT-IDPS促进IP 3 R介导的Ca 2+释放的能力密切相关。虽然总IP 3R表达水平在SU-DHL-4和OCI-LY-1中非常相似，但我们发现SU-DHL-4的IP 3R 2蛋白水平最高，而OCI-LY-1的IP 3R 2蛋白水平最低。引人注目的是，TAT-IDPS诱导的不同DL-BCL细胞系中的Ca 2+升高和凋亡与其IP 3R 2蛋白水平强烈相关，但与IP 3R 1、IP 3R 3或总IP 3R表达水平无关。抑制或敲低SU-DHL-4中的IP 3R 2活性减少了TAT-IDPS诱导的细胞凋亡，这与其使Bcl-2与IP 3R 2解离并促进IP 3诱导的促细胞凋亡Ca 2+信号传导的能力相一致。因此，某些慢性活化的B细胞淋巴瘤细胞依赖于高Bcl-2水平以使其存活，不仅中和促凋亡Bcl-2家族成员，而且抑制IP 3R过度活性。特别地，表达高水平IP 3R 2的癌细胞对IP 3R/Bcl-2复合物形成上瘾，并且使用肽工具破坏这些复合物导致促凋亡Ca 2+信号传导和细胞死亡。
Disrupting inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP3R-derived peptide (TAT-IDPS)) that selectively targets the BH4 domain of Bcl-2 but not that of B-cell lymphoma 2-extra large (Bcl-Xl) potentiated pro-apoptotic Ca2+ signaling in chronic lymphocytic leukemia cells. However, the molecular mechanisms rendering cancer cells but not normal cells particularly sensitive to disrupting IP3R/Bcl-2 complexes are poorly understood. Therefore, we studied the effect of TAT-IDPS in a more heterogeneous Bcl-2-dependent cancer model using a set of ‘primed to death' diffuse large B-cell lymphoma (DL-BCL) cell lines containing elevated Bcl-2 levels. We discovered a large heterogeneity in the apoptotic responses of these cells to TAT-IDPS with SU-DHL-4 being most sensitive and OCI-LY-1 being most resistant. This sensitivity strongly correlated with the ability of TAT-IDPS to promote IP3R-mediated Ca2+ release. Although total IP3R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP3R2-protein level was the highest for SU-DHL-4 and the lowest for OCI-LY-1. Strikingly, TAT-IDPS-induced Ca2+ rise and apoptosis in the different DL-BCL cell lines strongly correlated with their IP3R2-protein level, but not with IP3R1-, IP3R3- or total IP3R-expression levels. Inhibiting or knocking down IP3R2 activity in SU-DHL-4-reduced TAT-IDPS-induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP3R2 and to promote IP3-induced pro-apoptotic Ca2+ signaling. Thus, certain chronically activated B-cell lymphoma cells are addicted to high Bcl-2 levels for their survival not only to neutralize pro-apoptotic Bcl-2-family members but also to suppress IP3R hyperactivity. In particular, cancer cells expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca2+ signaling and cell death.
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影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen
影响因子：
11.2
作者：
Deng, Jing;Shimamura, Takeshi;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
3.4
作者：
Fukuda, Nanaho;Shirasu, Mika;Mikoshiba, Katsuhiko
通讯作者：
Mikoshiba, Katsuhiko
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony