WEE1 inhibition sensitizes basal breast cancer cells to TRAIL-induced apoptosis.
WEE1 inhibition sensitizes basal breast cancer cells to TRAIL-induced apoptosis.
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DOI：
10.1158/1541-7786.mcr-11-0500
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Lipkowitz S
中科院分区：
文献类型：
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作者：
Garimella SV;Rocca A;Lipkowitz S
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是TNF超家族的一员，已被证明在许多癌细胞系中诱导细胞凋亡，但在正常细胞中却没有。根据雌激素和孕激素受体的表达、HER-2扩增或缺乏这三种标志物（称为三阴性或基底型乳腺癌），乳腺癌可分为不同的亚组。我们的团队和其他人之前已经表明，三阴性乳腺癌细胞系对TRAIL敏感，而其他细胞系则相对耐药。在早期的一项研究中，我们报道了细胞周期检查点调节因子WEE1的抑制导致乳腺癌细胞系细胞死亡增加。在这项研究中，我们测试了WEE1抑制对trail介导的乳腺癌细胞系细胞凋亡的影响。与单独使用WEE1抑制剂或TRAIL治疗相比，预先使用WEE1抑制剂或敲低WEE1可增加TRAIL在基底/三阴性乳腺癌细胞系中的毒性。细胞死亡的增加是由于死亡受体表面表达增加，caspase激活增加，可被泛caspase抑制剂Z-VAD-FMK阻断，从而使细胞免于caspase介导的凋亡。细胞死亡主要是由caspase-8引发的，因为caspase-8的敲除而不是任何其他启动caspase（即caspase-2， -9或-10）的敲除将细胞从WEE1抑制剂致敏的trail诱导的细胞死亡中拯救出来。综上所述，这些数据表明，WEE1抑制剂和TRAIL联合使用可能为基础/三阴性乳腺癌的治疗提供一种新的组合。
Tumor Necrosis Factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL) is a member of the TNF super family and has been shown to induce apoptosis in many cancer cell lines but not in normal cells. Breast cancers can be divided into different subgroups based on the expression of estrogen and progesterone receptors, HER-2 amplification, or the lack of these three markers (known as triple-negative or basal-type breast cancer). Our group and others have shown previously that triple-negative breast cancer cell lines are sensitive to TRAIL while others are relatively resistant. In an earlier study, we reported that inhibition of WEE1, a cell cycle checkpoint regulator, causes increased cell death in breast cancer cell lines. In this study, we tested the effects of WEE1 inhibition on TRAIL-mediated apoptosis in breast cancer cell lines. Pre-treatment with WEE1 inhibitor or knockdown of WEE1 increased the toxicity of TRAIL in the basal/triple-negative breast cancer cell lines compared to WEE1 inhibitor or TRAIL treatment alone. The enhanced cell death is attributed to increased surface expression of death receptors, increased caspase activation which could be blocked by the pan-caspase inhibitor, Z-VAD-FMK, thereby rescuing cells from caspase-mediated apoptosis. The cell death was initiated primarily by caspase-8 since knockdown of caspase-8 and not of any other initiator caspases (i.e, caspase-2, -9, or -10) rescued cells from WEE1 inhibitor sensitized TRAIL-induced cell death. Taken together, the data suggest that the combination of WEE1 inhibitor and TRAIL could provide a novel combination for the treatment of basal/triple-negative breast cancer.