Mehdawi Lubna M, Satapathy Shakti Ranjan, Gustafsson Annika, Lundholm Kent, Alvarado-Kristensson Maria, Sjölander Anita
Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Oncotarget. 2017 May 23;8(21):35033-35047. doi: 10.18632/oncotarget.16591.
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Cyclooxygenase-2, which plays a key role in the biosynthesis of prostaglandin E2 (PGE2), is often up-regulated in CRC and in other types of cancer. PGE2 induces angiogenesis and tumor cell survival, proliferation and migration. The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE2 catabolism, converting it into its inactive metabolite 15-keto-PGE2, and is often down-regulated in cancer. Interestingly, CRC patients expressing high levels of the cysteinyl leukotriene 2 (CysLT2) receptor have a good prognosis; therefore, we investigated a potential link between CysLT2 signaling and the tumor suppressor 15-PGDH in colon cancer cells.We observed a significant up-regulation of 15-PGDH after treatment with LTC4, a CysLT2 ligand, in colon cancer cells at both the mRNA and protein levels, which could be reduced by a CysLT2 antagonist or a JNK inhibitor. LTC4 induced 15-PGDH promoter activity via JNK/AP-1 phosphorylation. Furthermore, we also observed that LTC4, via the CysLT2/JNK signaling pathway, increased the expression of the differentiation markers sucrase-isomaltase and mucin-2 in colon cancer cells and that down-regulation of 15-PGDH totally abolished the observed increase in these markers.In conclusion, the restoration of 15-PGDH expression through CysLT2 signaling promotes the differentiation of colon cancer cells, indicating an anti-tumor effect of CysLT2 signaling.
结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。环氧化酶-2在前列腺素E2（PGE2）的生物合成中起关键作用，在结直肠癌和其他类型的癌症中常上调。PGE2诱导血管生成以及肿瘤细胞存活、增殖和迁移。肿瘤抑制因子15-羟基前列腺素脱氢酶（15-PGDH）是PGE2分解代谢中的关键酶，可将其转化为无活性代谢物15-酮-PGE2，在癌症中常下调。有趣的是，高表达半胱氨酰白三烯2（CysLT2）受体的结直肠癌患者预后良好；因此，我们研究了结肠癌细胞中CysLT2信号与肿瘤抑制因子15-PGDH之间的潜在联系。我们观察到，用CysLT2配体LTC4处理后，结肠癌细胞中15-PGDH在mRNA和蛋白质水平均显著上调，而CysLT2拮抗剂或JNK抑制剂可降低这种上调。LTC4通过JNK/AP-1磷酸化诱导15-PGDH启动子活性。此外，我们还观察到，LTC4通过CysLT2/JNK信号通路增加结肠癌细胞中蔗糖酶-异麦芽糖酶和粘蛋白-2等分化标志物的表达，而15-PGDH的下调完全消除了这些标志物的观察到的增加。总之，通过CysLT2信号恢复15-PGDH表达可促进结肠癌细胞的分化，表明CysLT2信号具有抗肿瘤作用。
