Kim Sun-Hee, Hashimoto Yuuri, Cho Sung-Nam, Roszik Jason, Milton Denái R, Dal Fulya, Kim Sangwon F, Menter David G, Yang Peiying, Ekmekcioglu Suhendan, Grimm Elizabeth A
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Pigment Cell Melanoma Res. 2016 May;29(3):297-308. doi: 10.1111/pcmr.12455. Epub 2016 Mar 15.
COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels, and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1-specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy.
环氧化酶-2（COX-2）及其产物前列腺素E2（PGE2）可促进癌症发生和肿瘤进展，此前在黑色素瘤中已有相关报道。由于大多数COX抑制剂具有较大毒性，因此下游微粒体PGE2合酶-1（mPGES1）成为一个可供靶向的考虑对象。采用人黑色素瘤组织微阵列（TMAs）检测mPGES1蛋白染色强度和阳性率水平，二者均随临床分期增加而升高；采用另一组III期TMA，mPGES1强度（而非阳性率）与患者生存率降低相关。我们的结果进一步表明，在mPGES1水平较高的黑色素瘤组织中，诱导型一氧化氮合酶（iNOS）也高表达，且iNOS介导的一氧化氮（NO）促进mPGES1表达和PGE2生成。一种mPGES1特异性抑制剂（CAY10526）以及小干扰RNA（siRNA）可减弱细胞存活并增加细胞凋亡。CAY10526显著抑制黑色素瘤异种移植瘤的生长并增加细胞凋亡。我们的研究结果支持mPGES1具有预后和预测价值，并表明靶向PGE2途径中的该分子是改善黑色素瘤治疗的另一条途径。
