Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells
Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells
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DOI：
10.1007/s10495-016-1339-x
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发表时间：
2017-04-01
期刊：
影响因子：
7.2
通讯作者：
Alvero, Ayesha B.
中科院分区：
文献类型：
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作者：
Cardenas, Carlos;Montagna, Michele K.;Alvero, Ayesha B.
对卵巢癌启动的细胞凋亡的抗性是包括CD 44 +/MyD 88+上皮性卵巢癌（EOC）干细胞在内的化学抗性癌症干细胞的标志。这是由Bcl（2）蛋白家族的成员控制的，其作为线粒体稳定性的变阻器起作用。我们观察到Bcl（2）家族成员的差异表达谱，比较化疗耐药的EOC干细胞和化疗敏感的CD 44-/MyD 88- EOC细胞。与化学敏感性EOC细胞相比，化学抗性EOC干细胞令人惊讶地表达更高水平的促凋亡成员巴克和Bax。此外，尽管化学敏感性EOC细胞优先表达Bcl（2），但化学抗性EOC干细胞优先表达Bcl（xl）。在EOC干细胞中，Bcl（xl）表达的40%敲低足以诱导半胱天冬酶的完全激活，并且这可以通过同时敲低Puma来逆转。更重要的是，我们证明了Bcl（xl）在EOC细胞中的表达水平是动态的，并且可以通过富含促炎细胞因子IL-6的微环境（如癌症干细胞和脂肪细胞小生境）进行调节。脂肪细胞诱导的Bcl（xl）上调与获得化学抗性相关，因此证明了特定微环境如何调节凋亡蛋白的表达并赋予化学抗性。
Resistance to mitochondria-initiated apoptosis is a hallmark of chemoresistant cancer stem cells including CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells. This is controlled by members of the Bcl(2) family of proteins, which function as rheostats of mitochondrial stability. We observed a differential expression profile of Bcl(2) family members comparing the chemoresistant EOC stem cells and the chemosensitive CD44-/MyD88- EOC cells. Chemoresistant EOC stem cells surprisingly express higher levels of the pro-apoptotic members Bak and Bax compared to the chemosensitive EOC cells. In addition, whereas chemosensitive EOC cells preferentially express Bcl(2), chemoresistant EOC stem cells preferentially express Bcl(xl). In the EOC stem cells, 40% knock-down of Bcl(xl) expression was sufficient to induce the full activation of caspases and this can be reversed by concurrent knock-down of Puma. More importantly, we demonstrate that Bcl(xl) expression levels in EOC cells is dynamic and can be regulated by microenvironments that are enriched with the pro-inflammatory cytokine IL-6 such as the cancer stem cell and adipocyte niches. Adipocyte-induced upregulation of Bcl(xl) correlated with acquisition of chemoresistance and thus demonstrates how a specific microenvironment can regulate the expression of apoptotic proteins and confer chemoresistance.