Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells
Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells
复制标题
DOI：
10.1038/sj.onc.1210962
复制
发表时间：
2008-05-08
期刊：
影响因子：
8
通讯作者：
Hinz, B.
中科院分区：
文献类型：
--
作者：
Eichele, K.;Ramer, R.;Hinz, B.
环氧合酶-2（考克斯-2）在肿瘤中的作用仍存在争议。本研究以宫颈癌细胞（HeLa）为研究对象，探讨考克斯-2在紫杉醇、顺铂和5-氟尿嘧啶诱导的细胞凋亡中的作用。每种化合物导致考克斯-2表达和前列腺素（PG）合成的深刻诱导，伴随着活力的大幅下降和增强的凋亡。当考克斯-2表达或其活性分别被小干扰RNA（siRNA）和选择性考克斯-2抑制剂NS-398抑制时，细胞对凋亡的敏感性显著降低。为阐明考克斯-2如何导致细胞凋亡而进行的实验揭示了PGD 2及其脱水产物15-脱氧- D12，14 PGJ 2（15 d-PGJ 2）的深刻的促细胞凋亡作用。与这些发现一致，通过靶向脂质运载蛋白型PGD合酶（L-PGDS）的siRNA阻止化疗剂诱导的细胞凋亡，所述L-PGDS催化PGH 2异构化为PGD 2。此外，化疗剂、PGD 2和15 d-PGJ 2引起的细胞凋亡被过氧化物酶体增殖物激活受体c（PPARc）拮抗剂GW-9662或PPARc siRNA抑制。最后，在人肺癌细胞（A549）以及另一种宫颈癌细胞系（C33 A）中证实了所有研究的化疗药物的考克斯-2依赖性凋亡机制。总的来说，本研究表明，考克斯-2诱导和合成的L-PGDS衍生的，PPARc激活PG作为一个决定性的目标，其中几个化疗诱导细胞凋亡。因此，怀疑考克斯-2在某些情况下使癌细胞对凋亡性死亡敏感，这表明癌症治疗期间的考克斯-2抑制可降低其功效。
The role of cyclooxygenase-2 (COX-2) in cancer remains controversial. Using cervical carcinoma cells (HeLa), the present study investigates the involvement of COX-2 in apoptosis elicited by the chemotherapeutics paclitaxel, cisplatin and 5-fluorouracil. Each compound led to a profound induction of COX-2 expression and prostaglandin (PG) synthesis, accompanied by a substantial decrease of viability and enhanced apoptosis. Cells were significantly less sensitive to apoptotic death when either COX-2 expression or its activity was suppressed by smallinterfering RNA (siRNA) and by the selective COX-2 inhibitor NS-398, respectively. Experiments performed to clarify how COX-2 leads to apoptosis revealed a profound proapoptotic action of PGD2 and its dehydration product, 15-deoxy- D12,14 PGJ2 (15d-PGJ2). In line with these findings, chemotherapeutics-induced apoptosis was prevented by siRNA targeting lipocalin-type PGD synthase (L-PGDS), which catalyses the isomerization of PGH2 to PGD2. Moreover, apoptosis by chemotherapeutics, PGD2 and 15d-PGJ2 was suppressed by the peroxisome proliferator-activated receptor c (PPARc) antagonist, GW-9662 or PPARc siRNA. Finally, a COX-2-dependent apoptotic mechanism of all investigated chemotherapeutics was confirmed in human lung cancer cells (A549) as well as in another cervical carcinoma cell line (C33A). Collectively, this study suggests COX-2 induction and synthesis of L-PGDS-derived, PPARc-activating PGs as a decisive target by which several chemotherapeutics induce apoptosis. COX-2 is therefore suspected to sensitize cancer cells to apoptotic death under certain circumstances, suggesting that COX-2 inhibition during cancer therapy could diminish its efficacy.