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Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.

Zhou Y, Chang R, Ji W, Wang N, Qi M, Xu Y, Guo J, Zhan L - J. Biol. Chem. (2015)

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.

View Article: PubMed Central - PubMed

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.

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Loss of Scribble mediates drug resistance both in vivo and in vitro.A, protein levels of Scribble in the indicated cisplatin-resistant SKOV3/DDP cell lines (and respective parent lines) were detected by immunoblotting with anti-Scrib and HSP90. HSP90 served as a loading control, the MTT assay was used to assess the relative survival of cells harboring the control RNAi or Scribble RNAi after treatment with cisplatin at the indicated concentrations. Assays were performed in triplicate and the results are presented as the mean ± S.D. B, nude mice harboring tumors derived from implanted control A549 or A549 Scribble KD cells were treated by intraperitoneal injection with saline or 2.5 mg/kg of cisplatin. Tumor weights calculated are presented as the mean ± S.D. for each group (n = 4), and their weight plotted in comparison to mice. **, p < 0.01 (Student's t test). C, tumor dimensions were recorded; *, p < 0.05 (Student's t test). D, a model proposed mechanism for Scribble regulation of p38 MAPK activity and HuR translocation, resulting in increased Snail translation and promotion of drug resistance. P in circles indicates phosphorylation.
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Figure 7: Loss of Scribble mediates drug resistance both in vivo and in vitro.A, protein levels of Scribble in the indicated cisplatin-resistant SKOV3/DDP cell lines (and respective parent lines) were detected by immunoblotting with anti-Scrib and HSP90. HSP90 served as a loading control, the MTT assay was used to assess the relative survival of cells harboring the control RNAi or Scribble RNAi after treatment with cisplatin at the indicated concentrations. Assays were performed in triplicate and the results are presented as the mean ± S.D. B, nude mice harboring tumors derived from implanted control A549 or A549 Scribble KD cells were treated by intraperitoneal injection with saline or 2.5 mg/kg of cisplatin. Tumor weights calculated are presented as the mean ± S.D. for each group (n = 4), and their weight plotted in comparison to mice. **, p < 0.01 (Student's t test). C, tumor dimensions were recorded; *, p < 0.05 (Student's t test). D, a model proposed mechanism for Scribble regulation of p38 MAPK activity and HuR translocation, resulting in increased Snail translation and promotion of drug resistance. P in circles indicates phosphorylation.

Mentions: We have developed panels of a cisplatin-resistant cancer cell line, SKOV3/DDP, with acquired and inherent resistance to cisplatin. We further demonstrated that the SKOV3/DDP cell line had a lower Scribble protein level when compared with the parental cells. To directly test the in vivo Scribble function in cisplatin sensitivity, we performed xenografts experiments with control or the stable KD human lung cancer cell line A549 cells following cisplatin treatment. As shown in Fig. 7, B and C, among the cisplatin-treated animals, tumors in mice implanted with A549 Scribble KD cells remained significantly larger and grew faster. The present study suggests the importance of Scribble in cisplatin resistance.


Loss of Scribble Promotes Snail Translation through Translocation of HuR and Enhances Cancer Drug Resistance.

Zhou Y, Chang R, Ji W, Wang N, Qi M, Xu Y, Guo J, Zhan L - J. Biol. Chem. (2015)

Loss of Scribble mediates drug resistance both in vivo and in vitro.A, protein levels of Scribble in the indicated cisplatin-resistant SKOV3/DDP cell lines (and respective parent lines) were detected by immunoblotting with anti-Scrib and HSP90. HSP90 served as a loading control, the MTT assay was used to assess the relative survival of cells harboring the control RNAi or Scribble RNAi after treatment with cisplatin at the indicated concentrations. Assays were performed in triplicate and the results are presented as the mean ± S.D. B, nude mice harboring tumors derived from implanted control A549 or A549 Scribble KD cells were treated by intraperitoneal injection with saline or 2.5 mg/kg of cisplatin. Tumor weights calculated are presented as the mean ± S.D. for each group (n = 4), and their weight plotted in comparison to mice. **, p < 0.01 (Student's t test). C, tumor dimensions were recorded; *, p < 0.05 (Student's t test). D, a model proposed mechanism for Scribble regulation of p38 MAPK activity and HuR translocation, resulting in increased Snail translation and promotion of drug resistance. P in circles indicates phosphorylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697165&req=5

Figure 7: Loss of Scribble mediates drug resistance both in vivo and in vitro.A, protein levels of Scribble in the indicated cisplatin-resistant SKOV3/DDP cell lines (and respective parent lines) were detected by immunoblotting with anti-Scrib and HSP90. HSP90 served as a loading control, the MTT assay was used to assess the relative survival of cells harboring the control RNAi or Scribble RNAi after treatment with cisplatin at the indicated concentrations. Assays were performed in triplicate and the results are presented as the mean ± S.D. B, nude mice harboring tumors derived from implanted control A549 or A549 Scribble KD cells were treated by intraperitoneal injection with saline or 2.5 mg/kg of cisplatin. Tumor weights calculated are presented as the mean ± S.D. for each group (n = 4), and their weight plotted in comparison to mice. **, p < 0.01 (Student's t test). C, tumor dimensions were recorded; *, p < 0.05 (Student's t test). D, a model proposed mechanism for Scribble regulation of p38 MAPK activity and HuR translocation, resulting in increased Snail translation and promotion of drug resistance. P in circles indicates phosphorylation.
Mentions: We have developed panels of a cisplatin-resistant cancer cell line, SKOV3/DDP, with acquired and inherent resistance to cisplatin. We further demonstrated that the SKOV3/DDP cell line had a lower Scribble protein level when compared with the parental cells. To directly test the in vivo Scribble function in cisplatin sensitivity, we performed xenografts experiments with control or the stable KD human lung cancer cell line A549 cells following cisplatin treatment. As shown in Fig. 7, B and C, among the cisplatin-treated animals, tumors in mice implanted with A549 Scribble KD cells remained significantly larger and grew faster. The present study suggests the importance of Scribble in cisplatin 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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus