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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by reversing EMT
Weiwei Liu1, Xuchu Wang1, Yiyun Wang1
1Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Background:
Despite SGK1 has been identified and characterized as a tumor-promoting gene, the functions and underlying mechanisms of SGK1 involved in metastasis regulation have not yet been investigated in cancer.
Methods:
We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry.
Results:
In the present study, we found that SGK1 expression positively correlates with human prostate cancer (PCa) progression and metastasis. We show that SGK1 inhibition significantly attenuates EMT and metastasis both in vitro and in vivo, whereas overexpression of SGK1 dramaticlly promoted the invasion and migration of PCa cells. Our further results suggest that SGK1 inhibition induced antimetastatic effects, at least partially via autophagy-mediated repression of EMT through the downregulation of Snail. Moreover, ectopic expression of SGK1 obviously attenuated the GSK650394-induced autophagy and antimetastatic effects. What's more, dual inhibition of mTOR and SGK1 enhances autophagy and leads to synergistic antimetastatic effects on PCa cells.
Conclusions:
Taken together, this study unveils a novel mechanism in which SGK1 functions as a tumor metastasis-promoting gene and highlights how co-targeting SGK1 and autophagy restrains cancer progression due to the amplified antimetastatic effects.
Insights
Serum and glucocorticoid-regulated kinase 1 (SGK1) promotes prostate cancer metastasis by driving epithelial-mesenchymal transition (EMT). Inhibiting SGK1, especially with dual targeting of mTOR, reduces metastasis through autophagy, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- SGK1 is recognized as a tumor-promoting gene.
- Its specific role in cancer metastasis regulation remains largely unexplored.
Purpose of the Study:
- To investigate the function and mechanisms of SGK1 in prostate cancer (PCa) metastasis.
- To explore SGK1's role in regulating epithelial-mesenchymal transition (EMT) and autophagy.
Main Methods:
- Utilized human PCa cell lines and PC3 xenografts.
- Employed wound healing, migration, and invasion assays.
- Performed western blotting, immunofluorescence, and immunohistochemistry.
Main Results:
- SGK1 expression correlates with PCa progression and metastasis.
- SGK1 inhibition attenuated EMT and metastasis; SGK1 overexpression promoted invasion and migration.
- SGK1 inhibition induced anti-metastatic effects via autophagy-mediated EMT repression through Snail downregulation.
- Dual inhibition of mTOR and SGK1 synergistically enhanced anti-metastatic effects.
Conclusions:
- SGK1 acts as a novel metastasis-promoting gene in cancer.
- Co-targeting SGK1 and autophagy presents a promising strategy to restrain cancer progression by amplifying anti-metastatic effects.
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