Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of Bad in glioblastoma cells
Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of Bad in glioblastoma cells
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DOI：
10.1124/mol.106.031849
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发表时间：
2007-07-01
影响因子：
3.6
通讯作者：
Borea, Pier Andrea
中科院分区：
文献类型：
--
作者：
Merighi, Stefania;Benini, Annalisa;Borea, Pier Andrea
实体瘤含有耐放疗和化疗的缺氧细胞。胶质母细胞瘤的耐药性与抗凋亡Bcl-2家族成员的表达有关。在这项研究中，我们发现，在人类胶质母细胞瘤细胞缺氧诱导Bcl-2家族蛋白Bad的磷酸化，从而保护缺氧细胞免受紫杉醇诱导的凋亡。Akt的激活是缺氧保护所必需的。与此相反，细胞外信号调节激酶1/2的活动只有一个部分的效果，能够调节坏的磷酸化，但不是紫杉醇诱导的细胞凋亡缺氧。我们还证明了腺苷脱氨酶降解腺苷，基因沉默敲低A（3）腺苷受体表达，以及通过A（3）受体拮抗剂阻断该受体阻断缺氧诱导的Bad磷酸化，并延长紫杉醇处理后的细胞存活时间。因此，腺苷能信号转导可能是缺氧存活途径中的重要组成部分。这些结果表明，缺氧诱导的人胶质母细胞瘤细胞的化疗耐药性可能发生在一个新的机制，涉及激活腺苷-A（3）受体-Akt通路，介导Bad失活，有利于细胞存活。
Solid tumors contain hypoxic cells that are resistant to radiotherapy and chemotherapy. The resistance in glioblastoma has been linked to the expression of antiapoptotic Bcl-2 family members. In this study, we found that in human glioblastoma cells hypoxia induces the phosphorylation of the Bcl-2 family protein Bad, thus protecting hypoxic cells from paclitaxel-induced apoptosis. Akt activation is required for the hypoxia-induced protection. In contrast, the extracellular signal-regulated kinase 1/2 activities have only a partial effect, being able to modulate Bad phosphorylation but not paclitaxel-induced apoptosis in hypoxia. We also demonstrated that the degradation of adenosine with adenosine deaminase, the knockdown of A(3) adenosine receptor expression by gene silencing, and the blockade of this receptor through A(3) receptor antagonists blocked the hypoxia-induced phosphorylation of Bad and the prolonged cell survival after treatment with paclitaxel in hypoxia. Thus, the adenosinergic signaling may be an essential component in the hypoxia survival pathway. These results suggest that hypoxia-induced chemoresistance of human glioblastoma cells may occur in a novel mechanism involving activation of adenosine-A(3) receptor-Akt pathway, which mediates Bad inactivation and favors cell survival.