Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea.
Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea.
Molecules. 2019 Sep 19;24(18):3409. doi: 10.3390/molecules24183409.
Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent.
双硫仑已被用于治疗酗酒，并表现出抗肿瘤作用。然而，双硫仑抗肿瘤活性的细胞内机制尚不清楚。在这项研究中，我们专注于双硫仑通过致癌因子碳酸酐酶 CA12 及其相关转运体阴离子交换器 AE2 对肺癌细胞系 A549 的调节作用。随着时间的推移，双硫仑处理会降低 CA12 和 AE2 的表面表达。双硫仑处理不会改变 Na-碳酸氢盐共转运蛋白的表达，也不会影响自噬调节。双硫仑处理会以时间依赖性方式降低 A549 细胞的氯碳酸氢盐交换器活性，而静息 pH 值不变。AE2 的表达和活性以及 CA12 的表达也会随着双硫仑处理而降低。侵袭实验和细胞迁移实验表明，双硫仑可减弱 A549 细胞的侵袭和迁移。总之，AE2 及其辅助酶 CA12 的衰减以及双硫仑处理对癌细胞迁移的抑制作用为双硫仑作为抗癌剂的潜力提供了分子证据。
