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Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells

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Abstract

Cancer metastasis is considered a major challenge in cancer therapy. Recently, epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling has been shown to induce epithelial-mesenchymal transition (EMT) and thereby to promote cancer metastasis. However, the underlying mechanism has not been fully elucidated. We demonstrate that EGF can induce EMT in human prostate and lung cancer cells and thus promote invasion and migration. EGF-induced EMT has been characterized by the cells acquiring mesenchymal spindle-like morphology and increasing their expression of N-cadherin and fibronectin, with a concomitant decrease of E-cadherin. Both protein and mRNA expression of transcription factor Snail rapidly increases after EGF treatment. The knockdown of Snail significantly attenuates EGF-induced EMT, suggesting that Snail is crucial for this process. To determine the way that Snail is accumulated, we demonstrate (1) that EGF promotes the stability of Snail via inhibiting the activity of glycogen synthase kinase 3 beta (GSK-3β), (2) that protein kinase C (PKC) rather than the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is responsible for GSK-3β inhibition and (3) that GSK-3β inhibition promotes the transcription of Snail. Taken together, these results reveal that the PKC/GSK-3β signaling pathway controls both the stability and transcription of Snail, which is crucial for EMT induced by EGF in PC-3 and A549 cells. Our study suggests a novel signaling pathway for Snail regulation and provides a better understanding of growth-factor-induced tumor EMT and metastasis.

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Acknowledgments

This study was supported by grants from the National Program on Key Basic Research Project (973 Program) (no. 2011CB935800) and the National Natural Science Foundation of China (nos. 81272311 and 81071712).

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Microbial and Biochemical Pharmacy School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, People’s Republic of China

    Zong-cai Liu, Xiao-hui Chen, Hong-sheng Wang, Ge Zhang, Hao Wang, Dan-yang Chen, Rui Fang, Hao Liu & Jun Du

  2. The School of Biomedical Science, Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China

    Hai-xing Song

  3. Department of Pharmacology College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China

    Shao-hui Cai

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  1. Zong-cai Liu
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Correspondence to Shao-hui Cai or Jun Du.

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Liu, Zc., Chen, Xh., Song, Hx. et al. Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res 358, 491–502 (2014). https://doi.org/10.1007/s00441-014-1953-2

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