Abstract
BackgroundThe S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms–p70-S6K1, p85-S6K1 and p54-S6K2–in prostate cancer, as well as their potential as therapeutic targets.MethodsIn this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro.ResultsS6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line.ConclusionsThese findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2629-y) contains supplementary material, which is available to authorized users.
Highlights
The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin and act as key regulators of protein synthesis and cell growth
S6K knockdown inhibits cell viability S6Ks stable knockdown and overexpression in PC3-luc cells were confirmed by western blotting (Fig. 1 a-b)
S6K knockdown inhibits cell migration we investigated if S6K isoforms impacted the migration capacity of prostate cancer cells (Fig. 2)
Summary
The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. Prostate cancer has a good prognosis in its early stages, with most men living at least five years after diagnosis, the 5-year survival rate decreases drastically, to less than 30 %, when it reaches advanced and metastatic stages. This reveals the current urgency to identify factors involved in prostate cancer progression [2]. The S6K proteins are members of the AGC family of serine/threonine kinases and one of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) protein. Once activated by mTOR, the S6K proteins are able to phosphorylate targets as rpS6 (ribosomal protein S6), eIF4B (eukaryotic translation Initiation Factor 4B) and eEF2K
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