Department of Surgical Oncology, Roswell Park Cancer Institute and the University at Buffalo/State University of New York, Buffalo, NY 14263, USA.
Anticancer Agents Med Chem. 2013 May;13(4):584-94. doi: 10.2174/1871520611313040008.
Focal adhesion kinase (FAK), hyaluronan (HA), and hyaluronan synthase-3 (HAS3) have been implicated in cancer growth and progression. FAK inhibition with the small molecule inhibitor Y15 decreases colon cancer cell growth in vitro and in vivo. HAS3 inhibition in colon cancer cells decreases FAK expression and activation, and exogenous HA increases FAK activation. We sought to determine the genes affected by HAS and FAK inhibition and hypothesized that dual inhibition would synergistically inhibit viability. Y15 (FAK inhibitor) and the HAS inhibitor 4-methylumbelliferone (4-MU) decreased viability in a dose dependent manner; viability was further inhibited by treatment with Y15 and 4-MU in colon cancer cells. HAS inhibited cells treated with 2 μM of Y15 showed significantly decreased viability compared to HAS scrambled cells treated with the same dose (p < 0.05) demonstrating synergistic inhibition of viability with dual FAK/HAS inhibition. Microarray analysis showed more than 2-fold up- or down-regulation of 121 genes by HAS inhibition, and 696 genes by FAK inhibition (p < 0.05) and revealed 29 common genes affected by both signaling. Among the genes affected by FAK or HAS3 inhibition were genes, playing role in apoptosis, cell cycle regulation, adhesion, transcription, heatshock and WNT pathways. Thus, FAK or HAS inhibition decreases SW620 viability and affects several similar genes, which are involved in the regulation of tumor survival. Dual inhibition of FAK and HAS3 decreases viability to a greater degree than with either agent alone, and suggests that synergistic inhibition of colon cancer cell growth can result from affecting similar genetic pathways.
粘着斑激酶（FAK）、透明质酸（HA）和透明质酸合酶-3（HAS3）被认为与癌症的生长和进展有关。小分子抑制剂 Y15 抑制 FAK 可减少体外和体内结肠癌细胞的生长。结肠癌细胞中 HAS3 的抑制降低了 FAK 的表达和激活，外源性 HA 增加了 FAK 的激活。我们试图确定受 HAS 和 FAK 抑制影响的基因，并假设双重抑制会协同抑制活力。Y15（FAK 抑制剂）和 HAS 抑制剂 4-甲基伞形酮（4-MU）呈剂量依赖性降低活力；在结肠癌细胞中，用 Y15 和 4-MU 处理进一步抑制活力。与用相同剂量处理的 HAS 乱序细胞相比，用 2 μM 的 Y15 处理的 HAS 抑制细胞的活力明显降低（p < 0.05），表明双重 FAK/HAS 抑制具有协同抑制活力的作用。微阵列分析显示，HAS 抑制使 121 个基因的表达上调或下调超过 2 倍，FAK 抑制使 696 个基因的表达上调或下调超过 2 倍（p < 0.05），并揭示了 29 个受两种信号共同影响的基因。受 FAK 或 HAS3 抑制影响的基因包括参与细胞凋亡、细胞周期调节、黏附、转录、热休克和 WNT 途径的基因。因此，FAK 或 HAS3 的抑制降低了 SW620 的活力，并影响了几个相似的基因，这些基因参与了肿瘤生存的调节。FAK 和 HAS3 的双重抑制比单独使用任何一种药物更能降低活力，这表明协同抑制结肠癌细胞生长可以通过影响相似的遗传途径来实现。
