Fraser S P, Salvador V, Manning E A, Mizal J, Altun S, Raza M, Berridge R J, Djamgoz M B A
Imperial College of Science, Technology, and Medicine, Department of Biological Sciences, Sir Alexander Fleming Building, Imperial College Road, London, United Kingdom.
J Cell Physiol. 2003 Jun;195(3):479-87. doi: 10.1002/jcp.10312.
Previous work suggested that functional voltage-gated Na(+) channels (VGSCs) are expressed specifically in strongly metastatic cells of rat and human prostate cancer (PCa), thereby raising the possibility that VGSC activity could be involved in cellular behavior(s) related to the metastatic cascade. In the present study, the possible role of VGSCs in the lateral motility of rat PCa cells was investigated in vitro by testing the effect of modulators that either block or enhance VGSC activity. Two rat PCa cell lines of markedly different metastatic ability were used in a comparative approach: the strongly metastatic MAT-LyLu and the weakly metastatic AT-2 cell line, only the former being known to express functional VGSCs. Using both electrophysiological recording and a motility assay, the effects of two VGSC blockers (tetrodotoxin and phenytoin) and four potential openers (veratridine, aconitine, ATX II, and brevetoxin) were monitored on (a) Na(+) channel activity and (b) cell motility over 48 h. Tetrodotoxin (at 1 microM) and phenytoin (at 50 microM) both decreased the motility index of the MAT-LyLu cell line by 47 and 11%, respectively. Veratridine (at 20 microM) and brevetoxin (at 10 nM) had no effect on the motility of either cell line, whilst aconitine (at 100 microM) and ATX II (at 25 pM) significantly increased the motility of the MAT-LyLu cell line by 15 and 9%, respectively. Importantly, at the concentrations used, none of these drugs had effects on the proliferation or viability of either cell line. The results, taken together, would suggest strongly that functional VGSC expression enhances cellular motility of PCa cells. The relevance of these findings to the metastatic process in PCa is discussed.
先前的研究表明，功能性电压门控钠通道（VGSCs）在大鼠和人类前列腺癌（PCa）的高转移细胞中特异性表达，因此增加了VGSC活性可能参与与转移级联相关的细胞行为的可能性。在本研究中，通过测试阻断或增强VGSC活性的调节剂的作用，在体外研究了VGSCs在大鼠PCa细胞侧向运动中的可能作用。采用比较方法使用了两种转移能力明显不同的大鼠PCa细胞系：高转移的MAT-LyLu和低转移的AT-2细胞系，只有前者已知表达功能性VGSCs。使用电生理记录和运动分析，监测了两种VGSC阻滞剂（河豚毒素和苯妥英）和四种潜在开放剂（藜芦碱、乌头碱、ATX II和短裸甲藻毒素）对（a）钠通道活性和（b）48小时内细胞运动的影响。河豚毒素（1μM）和苯妥英（50μM）分别使MAT-LyLu细胞系的运动指数降低了47%和11%。藜芦碱（20μM）和短裸甲藻毒素（10 nM）对两种细胞系的运动均无影响，而乌头碱（100μM）和ATX II（25 pM）分别使MAT-LyLu细胞系的运动显著增加了15%和9%。重要的是，在所使用的浓度下，这些药物均未对两种细胞系的增殖或活力产生影响。综合这些结果，强烈表明功能性VGSC表达增强了PCa细胞的运动能力。讨论了这些发现与PCa转移过程的相关性。
