Up-regulation of cyclooxygenase-2 and apoptosis resistance by p38 MAPK in hypericin-mediated photodynamic therapy of human cancer cells
Up-regulation of cyclooxygenase-2 and apoptosis resistance by p38 MAPK in hypericin-mediated photodynamic therapy of human cancer cells
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DOI：
10.1074/jbc.m307591200
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发表时间：
2003-12-26
影响因子：
4.8
通讯作者：
Agostinis, P
中科院分区：
文献类型：
--
作者：
Hendrickx, N;Volanti, C;Agostinis, P
光动力疗法（PDT）是一种获批的抗癌疗法，通过光敏剂吸收可见光后光化学产生活性氧来杀死癌细胞，光敏剂选择性地在肿瘤中积累。我们报道了金丝桃素介导的人类癌细胞PDT导致诱导型环氧合酶-2（考克斯-2）的上调和随后PGE的释放（2）。对所涉及的信号通路的剖析揭示了p38 MAPK α和β的选择性激活在蛋白和信使水平介导了考克斯-2的上调。p38 MAPK抑制剂PD 169316可抑制PDT处理细胞中的考克斯-2表达，而在激酶抑制剂存在下，耐药PD 169316不敏感的p38 MAPK α和β亚型的过表达可恢复考克斯-2水平。PDT上调考克斯-2表达与核因子-κ B的转录调控无关。在转录停滞的细胞中，p38 MAPK抑制剂显著缩短了考克斯-2信使的半衰期，这表明p38 MAPK主要通过稳定考克斯-2转录物起作用。WT-p38 MAPK的过表达增加了细胞对PDT诱导的细胞凋亡的抵抗力，并且抑制该途径加剧了细胞死亡并阻止了PGE 2的分泌。因此，PDT与p38 MAPK的吡啶基咪唑抑制剂的组合可以通过阻断考克斯-2上调来改善PDT的治疗功效，所述COX-2上调通过释放生长因子和促血管生成因子以及通过使癌细胞对凋亡敏感来促进肿瘤生长。
Photodynamic Therapy (PDT) is an approved anticancer therapy that kills cancer cells by the photochemical generation of reactive oxygen species following absorption of visible light by a photosensitizer, which selectively accumulates in tumors. We report that hypericin-mediated PDT of human cancer cells leads to up-regulation of the inducible cyclooxygenase-2 (COX-2) enzyme and the subsequent release of PGE(2). Dissection of the signaling pathways involved revealed that the selective activation of p38 MAPK alpha and beta mediate COX-2 up-regulation at the protein and messenger levels. The p38 MAPK inhibitor, PD169316, abrogated COX-2 expression in PDT-treated cells, whereas overexpression of the drug-resistant PD169316-insensitive p38 MAPK alpha and beta isoforms restored COX-2 levels in the presence of the kinase inhibitor. Transcriptional regulation by nuclear factor-kappaB was not involved in COX-2 up-regulation by PDT. The half-life of the COX-2 messenger was drastically shortened by p38 MAPK inhibition in transcriptionally arrested cells, suggesting that p38 MAPK mainly acts by stabilizing the COX-2 transcript. Overexpression of WT-p38 MAPK increased cellular resistance to PDT-induced apoptosis, and inhibiting this pathway exacerbated cell death and prevented PGE2 secretion. Hence, the combination of PDT with pyridinyl imidazole inhibitors of p38 MAPK may improve the therapeutic efficacy of PDT by blocking COX-2 up-regulation, which contributes to tumor growth by the release of growth- and pro-angiogenic factors, as well as by sensitizing cancer cells to apoptosis.