BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death.
BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death.
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DOI：
10.1016/j.bbrc.2017.12.156
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发表时间：
2018-01-29
影响因子：
3.1
通讯作者：
Xiang J
中科院分区：
文献类型：
--
作者：
Mañas A;Chen W;Nelson A;Yao Q;Xiang J
蛋白酶体抑制剂，如硼替佐米和卡非佐米，被FDA批准用于治疗造血系统癌症，但最近的研究表明它们在治疗实体瘤方面具有巨大的潜力。BaxΔ2是一种独特的促凋亡Bax亚型，可促进非线粒体细胞死亡并使癌细胞对化疗敏感。然而，内源性BaxΔ2蛋白是不稳定的，并且容易被蛋白酶体降解。在这里，我们在具有不同Bax状态的结直肠癌细胞中筛选了一组蛋白酶体抑制剂。我们发现，所有测试的蛋白酶体抑制剂都能够阻断BaxΔ2降解，而不影响Baxα或Bcl-2蛋白的水平。在测试的抑制剂中，只有硼替佐米和卡非佐米能够诱导对应于不同Bax状态的差异性细胞死亡。在低纳摩尔浓度下，BaxΔ2阳性细胞的细胞死亡水平显著高于Baxα阳性或Bax α阴性细胞。此外，硼替佐米诱导BaxΔ2阳性细胞的细胞死亡主要依赖于caspase 8/3途径，与我们先前的研究一致。这些结果意味着BaxΔ2可以选择性地使癌细胞对蛋白酶体抑制剂敏感，从而增强其治疗结肠癌和其他实体瘤的潜力。
Proteasome inhibitors, such as bortezomib and carfilzomib, are FDA approved for the treatment of hemopoietic cancers, but recent studies have shown their great potential for treatment of solid tumors. BaxΔ2, a unique proapoptotic Bax isoform, promotes non-mitochondrial cell death and sensitizes cancer cells to chemotherapy. However, endogenous BaxΔ2 proteins are unstable and susceptible to proteasomal degradation. Here, we screened a panel of proteasome inhibitors in colorectal cancer cells with different Bax statuses. We found that all proteasome inhibitors tested were able to block BaxΔ2 degradation without affecting the level of Baxα or Bcl-2 proteins. Among the inhibitors tested, only bortezomib and carfilzomib were able to induce differential cell death corresponding to the distinct Bax statuses. BaxΔ2-positive cells had a significantly higher level of cell death at low nanomolar concentrations than Baxα-positive or Bax-negative cells. Furthermore, bortezomib-induced cell death in BaxΔ2-positive cells was predominantly dependent on the caspase 8/3 pathway, consistent with our previous studies. These results imply that BaxΔ2 can selectively sensitize cancer cells to proteasome inhibitors, enhancing their potential to treat colon cancer and other solid tumors.
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影响因子：
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