Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells
Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells
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DOI：
10.3892/ijo.2013.1945
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发表时间：
2013-07-01
影响因子：
5.2
通讯作者：
Calvaruso, Giuseppe
中科院分区：
文献类型：
--
作者：
Portanova, Patrizia;Notaro, Antonietta;Calvaruso, Giuseppe
Notch是一个跨膜受体家族，通过伽玛-分泌酶的蛋白水解性裂解激活靶向参与细胞发育、分化和肿瘤发生的基因。Notch信号在包括乳腺癌在内的多种癌症中被结构性激活，其上调通常与不良的临床结果有关。因此，用伽马分泌酶抑制剂(GSI)靶向Notch信号转导被认为是一种很有前途的癌症治疗策略。我们报道了γ-分泌酶抑制物-I(GSI-I)使人乳腺癌细胞对肿瘤坏死因子相关的凋亡诱导配体(TRAIL)介导的凋亡敏感。与ER阳性的MCF-7细胞相比，ER阴性的MDA-MB-231乳腺癌细胞GSI-I/TRAIL的抗增殖协同作用更强。在MDA-MB-231细胞中，GSI-I诱导DR4和DR5 TRAIL受体表达上调。这种作用似乎与转录因子AP1的激活有关，这是Notch抑制的结果，Notch-1沉默实验证明了这一点。联合治疗导致线粒体跨膜电位丧失和半胱氨酸氨基转移酶激活。Gsi-I单独和/或Gsi-I/TRAIL联合应用还可显著降低Survivin、c-IAP-2、BCI-x(L)、Bim(EL)和PACK的水平，上调促凋亡因子Bim(L)、Bim(S)和Noxa，增强两种药物的细胞毒活性。综上所述，这些结果首次表明GSI-I/TRAIL组合可能成为乳腺癌治疗的一种新的、潜在的有效工具。
Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by gamma-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with gamma-secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the gamma-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER-positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, BcI-x(L), Bim(EL) and pAKT) and upregulation of pro-apoptotic factors Bim(L), Bim(S) and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment.