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 test the effects of the polarity gene Scribble on the cellular process of apoptosis, we generated stable Scribble KD gene expression in different cancer cell lines. We observed that there was no significant difference in the percentage of apoptosis between Scribble KD cells and control cells by general culture conditions. The platinum chemotherapeutic agent cisplatin is the first-line for lung cancer patients (24). Surprisingly, following cisplatin treatment, Scribble KD lines exhibited significant attenuation in the percentage of apoptotic cells compared with control cells (Fig. 1A). Meanwhile, flow-cytometric analysis documented that G1 phase, S phase, and G2/M phase remained almost the same in control cells, Scribble KD cells, and Scribble overexpression cells. Consistent with previous data in mammary gland cells (9), it indicated that Scribble low expression had no significant effect on the regulation of cell cycle and proliferative activity (Fig. 1B). Moreover, cells engineered to overexpress Scribble exhibited significantly increased levels of apoptosis upon cisplatin treatment (Fig. 1C). Meanwhile, there is no significant difference in cell cycle distributions in Scribble overexpression HTB-177 cells when compared with control cells under cisplatin treatment (Fig. 1D). To determine whether Scribble KD cells developed resistance to cisplatin, cells were treated with different concentrations of cisplatin for 24 h. A cell viability assay revealed that the percentage of surviving cells was enhanced by Scribble KD (Fig. 1E). The 50% inhibition concentration (IC50) for cisplatin in control and Scribble KD cells was 16.28 ± 0.06 and 26.33 ± 6.08 μg/ml, respectively. These data suggested that loss of Scribble can enhance cellular drug resistance to cisplatin.
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.