Background:Although inhibition of SGK1 has been shown to delay cancer progression, the underlying mechanisms have not yet been elucidated.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 flow cytometry, western blotting, immunofluorescence, transmission electron microscopy and immunohistochemistry.Results:In the present study, we demonstrated that SGK1 inhibition, mediated by either GSK650394 or SGK1 shRNA, induced G2/M arrest, apoptosis and autophagy. Furthermore, 3MA-mediated autophagy inhibition attenuated SGK1 inhibition-induced apoptosis, suggesting that induction of autophagy precedes apoptosis. Moreover, ectopic expression of SGK1 significantly attenuated the GSK650394-induced effects. Suppression of mTOR and Foxo3a phosphorylation is critical for blockade of SGK1-induced autophagy and apoptosis, at least partially via pFoxo3a (S253)-LC3 and pFoxo3a (S253)-p27 interactions. Dual inhibition of mTOR and SGK1 enhances autophagy activation and leads to synergistic cytocidal effects in PCa cells.Conclusions:In summary, our findings show that SGK1 inhibition exhibits significant antitumour effects against PCa in vitro and in vivo. This study uncovered a novel mechanism of SGK1 inhibition in PCa, which is mediated, at least in part, by inducing autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.

BackgroundDespite 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.MethodsWe 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.ResultsIn 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.ConclusionsTaken 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0743-1) contains supplementary material, which is available to authorized users.

Androgen deprivation therapy (ADT, surgical or chemical castration) is the mainstay treatment for metastatic prostate cancer (PCa); however, patients ineluctably relapse despite extremely low androgen levels. This evolution of PCa indicates its lethal progression. In this study, to mimic the traits of clinical PCa progression in vitro, we investigated the alterations in the cell biological characteristics in androgen-independent LNCaP cells (LNCaP-AI cells) compared with LNCaP cells. We also examined the effects of androgen on LNCaP and LNCaP-AI cell proliferation, androgen receptor (AR) expression and prostate-specific antigen (PSA) secretion. Furthermore, AR was silenced in the LNCaP and LNCaP-AI cells to detect the roles that AR plays in cell growth, apoptosis and PSA secretion. We found that prolonged androgen ablation increased the LNCaP-AI cell growth rate and cell invasiveness, and induced epithelial-mesenchymal transition in the LNCaP-AI cells. Moreover, despite the fact that the LNCaP and LNCaP-AI cells expressed equal amounts of AR protein, androgen induced a greater secretion of PSA in the LNCaP-AI cells than in the LNCaP cells. The proliferation of the LNCaP-AI cells was not dependent on, but was suppressed by androgen, which led to arrest at the G1 phase. Conversely, androgen significantly increased LNCaP cell proliferation by promoting the G1-S transition. Moreover, the silencing of AR suppressed LNCaP and LNCaP-AI cell growth by inducing cell cycle arrest at the G1 phase rather than promoting apoptosis, and reduced PSA secretion. On the whole, our data suggest that LNCaP-AI cells have a more more aggressive phenotype compared with the LNCaP cells; AR remains a critical factor in the LNCaP-AI cells, and androgen suppresses LNCaP-AI cell growth by blocking the cell cycle at the G1 phase.

The primary cause of tumor-associated mortality in prostate cancer (PCa) remains distant metastasis. The dissemination of tumor cells from the primary tumor to distant sites through the bloodstream cannot be detected early by standard imaging methods. Circulating tumor cells (CTCs) represent an effective prognostic and predictive biomarker, which are able to monitor efficacy of adjuvant therapies, detect early development of metastases, and finally, assess therapeutic responses of advanced disease earlier than traditional diagnostic methods. In addition, since repeated tissue biopsies are invasive, costly and not always feasible, the assessment of tumor characteristics on CTCs, by a peripheral blood sample as a liquid biopsy, represents an attractive opportunity. The implementation of molecular and genomic characterization of CTCs may contribute to improve the treatment selection and thus, to move toward more precise diagnosis and therapy in PCa. The present study summarizes the current advances in CTC enrichment and detection strategies and reviews how CTCs may contribute to significant insights in the metastatic process, as well as how they may be utilized in clinical application in PCa. Although it is proposed that CTCs may offer insights into the prognosis and management of PCa, there are a number of challenges in the study of circulating tumor cells, and their clinical utility remains under investigation.

Prostate cancer (PCa) is a metastatic malignant cancer driven by complex pathological mechanisms and characterized by poor long-term prognosis. Metastasis is the main cause of death of PCa patients, yet the molecular mechanisms of this process are poorly understood. In the present study, positive co-expression of RON and c-Met was observed in human clinical PCa tissues (biopsy material), as detected by immunohistochemical staining and quantitative real-time PCR. We investigated this further in PCa cells, demonstrating that the inhibition of RON and c-Met with foretinib (GSK1363089) suppressed metastasis and promoted the reversal of the epithelial-to-mesenchymal transition (EMT) in PCa cells. Furthermore, the invasion and migration of PCa cells were enhanced by the exogenous activation of RON with MSP and c-Met with HGF, whereas silencing of RON and c-Met attenuated the invasion and metastasis of the PCa cells. Our data also demonstrated that HGF/c-Met, but not the MSP-RON signaling pathway may be the dominant mechanism for PCa EMT. We further revealed that RON and c-Met facilitate metastasis via ERK1/2 signaling. These findings indicate that RON and c-Met facilitate metastasis through ERK1/2 signaling and that targeting RON and c-Met with foretinib may be an attractive therapeutic option for suppressing PCa metastasis.