Kandouz Mustapha, Nie Daotai, Pidgeon Graham P, Krishnamoorthy Sriram, Maddipati Krishna Rao, Honn Kenneth V
Department of Radiation Oncology, Wayne State University, 431 Chemistry Bldg., Detroit, MI 48202, USA.
Prostaglandins Other Lipid Mediat. 2003 Jul;71(3-4):189-204. doi: 10.1016/s1098-8823(03)00042-x.
Platelet-type arachidonate 12-lipoxygenase (12-LOX) is highly expressed in many types of cancers and plays an important role in cancer pathophysiology. Arachidonic acid metabolism by 12-LOX results in the stable end product 12(S)-hydroxy eicosatetraenoic acid (12(S)-HETE), which is a signaling molecule with effects on cell proliferation, motility, invasiveness, angiogenesis, and inhibition of apoptosis. The myriad biological activities manifested by 12(S)-HETE appear to be mediated, at least in part, by the activation of NF-kappaB. Overexpression of the 12-LOX in PC-3 prostate cancer cells resulted in the constitutive activation of the transcription factor. The enzymatic product of arachidonic acid metabolism, 12(S)-HETE, mediates the activation of NF-kappaB by the 12-LOX. 12(S)-HETE treatment of PC-3 cells induced the degradation of IkappaB by the S6 proteasomal pathway and the activated NF-kappaB translocated to the nucleus causing kappaB-induced transcription. Specificity of the NF-kappaB activation by 12(S)-HETE was established by the use of a 12-LOX-specific inhibitor and 13(S)-HODE, a known 12(S)-HETE antagonist. Considering the known involvement of MAP kinase pathway in NF-kappaB activation and that of 12(S)-HETE in MAP kinase pathway, 12-LOX present in prostate cancer tissues may contribute to the constitutive activation of NF-kappaB in prostate cancer cells.
血小板型花生四烯酸12-脂氧合酶（12-LOX）在多种癌症中高表达，在癌症病理生理学中发挥重要作用。12-LOX催化花生四烯酸代谢产生稳定的终产物12(S)-羟基二十碳四烯酸（12(S)-HETE），它是一种信号分子，对细胞增殖、运动、侵袭、血管生成及抑制细胞凋亡均有影响。12(S)-HETE所表现出的众多生物学活性似乎至少部分是由核因子κB（NF-κB）的激活介导的。在PC-3前列腺癌细胞中12-LOX的过表达导致了转录因子的组成性激活。花生四烯酸代谢的酶产物12(S)-HETE介导了12-LOX对NF-κB的激活。用12(S)-HETE处理PC-3细胞可通过S6蛋白酶体途径诱导IκB降解，激活的NF-κB易位至细胞核导致κB诱导的转录。通过使用12-LOX特异性抑制剂和已知的12(S)-HETE拮抗剂13(S)-HODE确定了12(S)-HETE激活NF-κB的特异性。鉴于已知丝裂原活化蛋白激酶（MAP）激酶途径参与NF-κB激活以及12(S)-HETE参与MAP激酶途径，前列腺癌组织中存在的12-LOX可能有助于前列腺癌细胞中NF-κB的组成性激活。
