Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.
Bottom Line: Furthermore, we demonstrate HuR can recognize AU-rich elements of the Snail-encoding mRNA, thereby regulating Snail translation.Moreover, loss of Scribble-induced HuR translocation mediates the accumulation of Snail via activation of the p38 MAPK pathway.Thus, this work clarifies the role of polarity protein Scribble, which is directly implicated in the regulation of developmental transcription factor Snail, and suggesting a mechanism for Scribble mediating cancer drug resistance.
Affiliation: From the Key Laboratory of Nutrition and Metabolism, Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.Show MeSH
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Mentions: To assess the role of HuR in drug resistance to cisplatin. We constructed a stable HuR KD cell line. We observed that KD HuR resulted in reduced Snail protein levels (Fig. 4A). Additionally, Snail accumulation was also decreased in cisplatin-treated HuR KD cells (Fig. 4A). To determine the role of HuR in cisplatin-related resistance to cisplatin, we performed a cell viability assay. We found that HuR KD cells had restored sensitivity to cisplatin when CRL-1848 HuR KD cells were treated with different concentrations of cisplatin for 24 h. The 50% inhibition concentration (IC50) for cisplatin in control and HuR KD cells was 14.09 ± 0.81 and 6.05 ± 0.37 μg/ml, respectively. It revealed that the percentage of surviving cells was reduced by HuR KD. We demonstrated that HuR KD can increase cisplatin-induced apoptosis by using an annexin V apoptosis detection kit (Fig. 4C). Ectopic overexpression of Snail in HuR KD cells partially attenuated HuR KD increased apoptosis during cisplatin treatment (Fig. 4C). Taken together, these results revealed that HuR KD can increase cisplatin-induced apoptosis through down-regulation of the Snail protein.
Affiliation: From the Key Laboratory of Nutrition and Metabolism, Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.