Hashimoto Y, Shimada Y, Itami A, Ito T, Kawamura J, Kawabe A, Kaganoi J, Maeda M, Watanabe G, Imamura M
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-Cho, Sakyo-Ku, Kyoto 606-8507, Japan.
Eur J Cancer. 2003 Oct;39(15):2239-46. doi: 10.1016/s0959-8049(03)00599-9.
Peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimerises with retinoid X receptor alpha (RXRalpha) and is thought to be a novel therapeutic target for human malignancies. We evaluated the ability of troglitazone (TRO) alone or in combination with 9-cis retinoic acid (9CRA), ligands of PPARgamma and RXRalpha, respectively, to inhibit the growth of oesophageal squamous cell carcinoma (OSCC). All 10 tested OSCC cell lines of a KYSE series expressed PPARgamma and RXRalpha at both the mRNA and protein levels. In four tested cell lines, TRO inhibited growth, and a synergistic effect was observed with simultaneous 9CRA application. In KYSE 270 cells, a luciferase reporter assay showed that the simultaneous application of TRO and 9CRA to the cells increased the relative luciferase activity approximately 20-fold compared with the controls without TRO or 9CRA application. In this cell line, flow cytometry demonstrated that combined treatment with TRO and 9CRA greatly increased the sub-G1 phase, and Hoechst 33342/propidium iodide (PI) staining showed that apoptotic cell death was mainly induced through ligand treatment. In addition, implanted tumours in nude mice showed significant inhibition of tumour growth when treated with TRO. These results suggest that the PPARgamma/RXRalpha heterodimer may be a new therapeutic target for OSCC.
过氧化物酶体增殖物激活受体γ（PPARγ）与视黄酸X受体α（RXRα）形成异源二聚体，被认为是人类恶性肿瘤的一个新的治疗靶点。我们评估了单独使用曲格列酮（TRO）或与PPARγ和RXRα的配体9-顺式维甲酸（9CRA）联合使用对食管鳞状细胞癌（OSCC）生长的抑制能力。所有10种测试的KYSE系列OSCC细胞系在mRNA和蛋白质水平均表达PPARγ和RXRα。在4种测试细胞系中，TRO抑制生长，同时应用9CRA时观察到协同效应。在KYSE 270细胞中，荧光素酶报告基因检测显示，与未应用TRO或9CRA的对照组相比，同时向细胞应用TRO和9CRA可使相对荧光素酶活性增加约20倍。在该细胞系中，流式细胞术表明TRO和9CRA联合处理可显著增加亚G1期，Hoechst 33342/碘化丙啶（PI）染色显示凋亡性细胞死亡主要是通过配体处理诱导的。此外，裸鼠体内植入的肿瘤在用TRO处理时显示出肿瘤生长的显著抑制。这些结果表明PPARγ/RXRα异源二聚体可能是OSCC的一个新的治疗靶点。
