Lee Yee-Shin, Chin Yu-Tang, Yang Yu-Chen S H, Wei Po-Li, Wu Han-Chung, Shih Ai, Lu Yueh-Tong, Pedersen Jens Z, Incerpi Sandra, Liu Leroy F, Lin Hung-Yun, Davis Paul J
Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
Steroids. 2016 Jul;111:63-70. doi: 10.1016/j.steroids.2016.03.006. Epub 2016 Mar 12.
Thyroid hormone induces cancer cell proliferation through its cell surface receptor integrin αvβ3. Acting via integrin αvβ3, the deaminated T4 analog tetraiodothyroacetic acid (tetrac), and its nanoparticle formulation nano-diamino-tetrac (NDAT) could inhibit cell proliferation and xenograft growth. In this study, we investigated the T4 effects on proliferation in colorectal cancer cell lines based on the proliferation marker expressions at both mRNA and protein levels. The effects of tetrac/NDAT, the monoclonal anti-EGFR antibody cetuximab, and their combinations on colorectal cancer cell proliferation were examined according to the relevant gene expression profiles and cell count analysis. The results showed that T4 significantly enhanced PCNA, Cyclin D1 and c-Myc levels in both K-ras wild type HT-29 and mutant HCT 116 cells. In HCT 116 cells, the combination of NDAT and cetuximab significantly suppressed the mRNA expressions of proliferative genes PCNA, Cyclin D1, c-Myc and RRM2 raised by T4 compared to cetuximab alone. In addition, T4-suppressed mRNA expressions of pro-apoptotic genes p53 and RRM2B could be significantly elevated by the combination of NDAT and cetuximab compared to cetuximab alone. In the K-ras mutant HCT 116 cells, but not in the K-ras wild type COLO 205 cells, the combinations of tetrac/NDAT and cetuximab significantly reduced cell proliferation compared to cetuximab alone. In conclusion, T4 promoted colorectal cancer cell proliferation which could be repressed by tetrac and NDAT. The combinations of tetrac/NDAT and cetuximab potentiated cetuximab actions in K-ras mutant colorectal cancer cells.
甲状腺激素通过其细胞表面受体整合素αvβ3诱导癌细胞增殖。脱氨基T4类似物四碘甲状腺乙酸（tetrac）及其纳米颗粒制剂纳米二氨基四碘甲状腺乙酸（NDAT）通过整合素αvβ3发挥作用，可抑制细胞增殖和异种移植瘤生长。在本研究中，我们基于增殖标志物在mRNA和蛋白质水平的表达，研究了T4对结肠癌细胞系增殖的影响。根据相关基因表达谱和细胞计数分析，检测了tetrac/NDAT、抗表皮生长因子受体单克隆抗体西妥昔单抗及其组合对结肠癌细胞增殖的影响。结果显示，T4显著提高了K-ras野生型HT-29细胞和突变型HCT 116细胞中增殖细胞核抗原（PCNA）、细胞周期蛋白D1和c-Myc的水平。在HCT 116细胞中，与单独使用西妥昔单抗相比，NDAT与西妥昔单抗联合使用可显著抑制T4上调的增殖相关基因PCNA、细胞周期蛋白D1、c-Myc和核糖核苷酸还原酶M2（RRM2）的mRNA表达。此外，与单独使用西妥昔单抗相比，NDAT与西妥昔单抗联合使用可显著提高T4下调的促凋亡基因p53和RRM2B的mRNA表达。在K-ras突变的HCT 116细胞中，但在K-ras野生型COLO 205细胞中未观察到，与单独使用西妥昔单抗相比，tetrac/NDAT与西妥昔单抗联合使用可显著降低细胞增殖。总之，T4促进结肠癌细胞增殖，而tetrac和NDAT可抑制该过程。tetrac/NDAT与西妥昔单抗联合使用可增强西妥昔单抗对K-ras突变结肠癌细胞的作用。
