Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling
Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling
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DOI：
10.1038/sj.onc.1209564
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发表时间：
2006-09-14
期刊：
影响因子：
8
通讯作者：
Phang, J. M.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Borchert, G. L.;Phang, J. M.
脯氨酸氧化酶（POX）通常被视为一种“管家酶”，可能在细胞凋亡中起重要作用。我们已经表明，POX产生依赖脯氨酸的活性氧物质（ROS），特别是超氧自由基，并通过线粒体（内在）途径诱导细胞凋亡。在我们目前的报告中，我们使用了在四环素诱导型启动子控制下稳定转染了POX基因的DLD - 1结直肠癌细胞，发现POX刺激了肿瘤坏死因子相关凋亡诱导配体（TRAIL）、DR5的表达以及半胱天冬酶 - 8的切割。重要的是，通过流式细胞术测量的细胞凋亡被半胱天冬酶 - 8的特异性抑制剂Z - IETD - FMK部分抑制。这些发现表明，外在（死亡受体）途径也被POX激活。此外，这种对外在途径影响的机制，特别是POX对TRAIL的诱导，可能由NFAT转录因子介导。此外，POX的表达还显著降低了MEK和ERK的磷酸化，并且这种降低被锰超氧化物歧化酶（MnSOD）的表达部分逆转。组成型激活形式的MEK（acMEK）的过表达部分阻断了POX诱导的细胞凋亡。这些发现表明MEK/ERK信号通路参与其中，并进一步证实了ROS/超氧化物在POX诱导的细胞凋亡中的作用。结合先前发表的数据，我们得出结论，POX可能通过内在和外在途径诱导细胞凋亡，并参与活化T细胞的核因子（NFAT）信号传导以及MEK/ERK途径的调节。有人提出，作为一种营养因子，POX可能调节由p53或其他抗癌药物诱导的细胞凋亡信号，并在应激情况下增强细胞凋亡。
Proline oxidase (POX), often considered a 'housekeeping enzyme' might play an important role in apoptosis. We have shown that POX generated proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, and induced apoptosis through the mitochondrial (intrinsic) pathway. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found POX-stimulated expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), DR5 and cleavage of caspase-8. Importantly, apoptosis measured by flow cytometry was partially inhibited by Z-IETD-FMK, a specific inhibitor of caspase-8. These findings suggest that the extrinsic (death receptor) pathway also is activated by POX. Furthermore, the mechanism of this effect on the extrinsic pathway, specifically, the induction of TRAIL by POX, may be mediated by NFAT transcription factors. Additionally, POX expression also dramatically decreased phosphorylation of MEK and ERK, and the decrease was partially reversed by expression of manganese superoxide dismutase (MnSOD). Overexpression of constitutively active form of MEK, acMEK, partially blocked POX-induced apoptosis. These findings suggest the involvement of MEK/ERK signaling and further confirm the role of ROS/superoxides in POX-induced apoptosis. Combined with previously published data, we conclude that POX may induce apoptosis through both intrinsic and extrinsic pathways and is involved in nuclear factor of activated T cells (NFAT) signaling and regulation of the MEK/ERK pathway. It is suggested that, as a nutrition factor, POX may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations.