| One of major obstacles for successful tumor chemotherapy is the development of acquired drug resistance, namely multiple-drug resistance (MDR). Studies have shown that MDR cells not only possess a property of cross drug resistance, but also acquire aberrant metastatic capacity.The hedgehog (Hh) signaling system conserved in organisms ranging from insects to mammals plays a crucial role in embryonic development, as well as post-embryonic tissue homeostasis through influences on stem or progenitor cells. Inappropriate Hh pathway activity has been demonstrated to be critical for initiation and progression of various kinds of tumors as well as maintaining the chemoresistant phenotype of acquired chemoresistant cancer cells.Smo, a key component in Hh signaling pathway, which possesses a structural similarity with that of G-protein coupled receptors (GPCR), has long been suggested to couple with heterotrimeric G proteins. Indeed, it has been shown that Smo may interact with Gai and subsequently acitivate the transcriptional activity of Gli (Ci in drosophila cells) in Drosophila C18cells, Sf9cells, and NIH3T3cells, indicating the requirement of Gai for the activation of Gli mediated by Smo. However, the role of Gai subunit in hedgehog pathway remains unclear.In this study, utilizing well established acquired chemoresistant cancer cell lines K562/A02or KB/VCR and respective parental ones K562or KB, we provide a series of complimentary evidences to show that Smo may utilize Gai for transducing the signaling to Gli and is essential for Hh mediated acquired chemoresistance in chemosensitive cancer cells, which harbor cell-autonomous Hh pathway activity. Moreover, we found that Gβγ, after released from Gai, may as well be involved in the Gli activation and acquired chemoresistance through activating JNK. Indeed, by artificially increasing the Hh pathway activity in chemosensitive cancer cells, we determined that both Gai and Gβγ-JNk signaling axis are required for the Gli activity and Gli-dependent chemoresistance mediated by SmoAl.For metastasis from a primary tumor site, cancer cells must lose cell-cell adhesion and acquire motility to invade adjacent cell layers. This process shares many similarities with epithelial-mesenchymal transition (EMT). Our findings confirm that JNK is involved in the chemoresistance mediated by Hh pathway. In addition to possess cross drug resistance characteristic, emerging evidences have shown that multiple-drug resistance (MDR) cancer cells exhibit aberrant metastatic capacity when compared to parental cells. In this study, we explored the contribution of c-Jun N-terminal kinases (JNK) signaling to the mesenchymal phenotypes and the aberrant motile capacity of MDR cells utilizing a well characterized MDR cell line KB/VCR and its parental cell line KB. Taking advantage of experimental strategies including pharmacological tool and gene knockdown, we showed here that interference with JNK signaling pathway by targeting JNK1/2or c-Jun reversed the mesenchymal properties of KB/VCR cells to epithelial phenotypes and suppressed the motile capacity of KB/VCR cells, such as migration and invasion. These observations support a critical role of JNK signaling in maintaining the mesenchymal of KB/VCR cells. Furthermore, we observed that JNK signaling may control the expression of both snail and twist1in KB/VCR cells, indicating that both snail and twistl are involved in controlling the mesenchymal characteristics of KB/VCR cells by JNK signaling. We demonstrated that JNK signaling may strictly be required for maintaining the mesenchymal properties of KB/VCR cells and its aberrant motile capacity through acting on snail and twistl.
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