Ropivacaine inhibits the migration of esophageal cancer cells via sodium-channel-independent but prenylation-dependent inhibition of Rac1/JNK/paxillin/FAK

Abstract

The direct anti-proliferative and pro-apoptotic effects of local anesthetics have been well documented in various cancers. However, whether local anesthetics affect cancer metastasis and their underlying molecular mechanisms are not well understood. In this work, we show that ropivacaine at the clinically relevant concentration significantly inhibits esophageal cancer cell migration. Interestingly, ropivacaine at the same concentration does not display inhibitory effects on esophageal cancer cell growth and survival. We further demonstrate that ropivacaine significantly decreases activities of GTPases including RhoA, Rac1 and Ras, and inhibits prenylation in esophageal cancer cells. In addition, the inhibitory effects of ropivacaine on GTPases activities and migration are abolished in the presence of geranylgeraniol and farnesol, demonstrating that ropivacaine inhibits GTPases activities via prenylation inhibition. Finally, we demonstrate that ropivacaine-inhibited esophageal cancer cell inhibition occurs independently of sodium channel but via suppressing Rac1/JNK/paxillin/FAK pathway. Our work demonstrates the potent anti-migratory effect of ropivacaine in esophageal cancer by attenuating prenylation-dependent migratory signalling events. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect metastasis.