p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells.
ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer and frequently metastasizes to LNs. Identifying metastasis-promoting factors is of immense clinical interest, as the prognosis for patients with even a single unilateral LN metastasis is extremely poor. Here, we report that p90 ribosomal S6 kinase 2 (RSK2) promotes human HNSCC cell invasion and metastasis. We determined that RSK2 was overexpressed and activated in highly invasive HNSCC cell lines compared with poorly invasive cell lines. Expression of RSK2 also correlated with metastatic progression in patients with HNSCC. Ectopic expression of RSK2 substantially enhanced the invasive capacity of HNSCC cells, while inhibition of RSK2 activity led to marked attenuation of invasion in vitro. Additionally, shRNA knockdown of RSK2 substantially reduced the invasive and metastatic potential of HNSCC cells in vitro and in vivo in a xenograft mouse model, respectively. Mechanistically, we determined that cAMP-responsive element-binding protein (CREB) and Hsp27 are phosphorylated and activated by RSK2 and are important for the RSK2-mediated invasive ability of HNSCC cells. Our findings suggest that RSK2 is involved in the prometastatic programming of HNSCC cells, through phosphorylation of proteins in a putative signaling network. Moreover, targeting RSK2 markedly attenuates in vitro invasion and in vivo metastasis of HNSCC cells, suggesting that RSK2 may represent a therapeutic target in the treatment of metastatic HNSCC.
Full-textDOI: · Available from: Fadlo R Khuri, May 05, 2015
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Article: p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells.
SourceAvailable from: Alicja Grudowska[Show abstract] [Hide abstract]
ABSTRACT: The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Herein, we have studied an involvement of RSKs in FGF2/FGFR2-driven behaviours of mammary epithelial and breast cancer cells. We found that both silencing and inhibiting of FGFR2 attenuated phosphorylation of RSKs, whereas FGFR2 overexpression and/or its stimulation with FGF2 enhanced RSKs activity. Moreover, treatment with ERK, Src and p38 inhibitors revealed that p38 kinase acts as an upstream RSK2 regulator. We demonstrate for the first time that in FGF2/FGFR2 signalling, p38 but not MEK/ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359/Ser363, Thr573 and Ser380). In contrast to FGF2-triggered signalling, inhibition of p38 in the EGF pathway affected only RSK2-Tyr529, without any impact on the remaining RSK phosphorylation sites. p38-mediated phosphorylation of RSK2-Tyr529 was crucial for transactivation of residues located at kinase C-terminal domain and linker-region, specifically, in the FGF2/FGFR2 signalling pathway. Furthermore, we show that FGF2 promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration, which was effectively abolished by treatment with RSKs inhibitor (FMK). These indicate that RSK2 activity is indispensable for FGF2/FGFR2-mediated cellular effects. Our findings identified a new FGF2/FGFR2-p38-RSK2 pathway which may play a significant role in the pathogenesis and progression of breast cancer, and hence, may present a novel therapeutic target in the treatment of FGFR2-expressing tumours.Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 07/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.06.022 · 5.30 Impact Factor
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ABSTRACT: Head and neck tumors belong among the six leading causes of cancer death worldwide. The predominant type of head and neck tumors consists of squamous cell carcinomas (HNSCC). Early detection of primary tumor and relapse is a key factor for enhancing the survival rate of HNSCC patients, because high rates of cases are recognized at advanced stages. Accordingly, biomarkers suitable for the early detection of HNSCC are sorely needed to improve patient outcomes. HNSCC evolve through a multistep process by the accumulation of genetic and phenotypic changes. Searching for specific biomarkers capable of characterizing each degree is therefore really essential. In this review, genomic and gene expression alterations of HNSCC are summarized and associated with HPV status, clinicopathological conditions, and patient history from the perspective of potential biomarker utilization. The emphasis is placed on non-invasive markers detectable from saliva and blood and clinically relevant studies are mentioned in particular. These include analyses of tumorous tissues, saliva, and blood from patients with histologically defined tumors; cell culture- and other in vitro-based studies with no clinical correlations are rather excluded.Oral Oncology 02/2014; 50(3):168-177. DOI:10.1016/j.oraloncology.2013.12.008 · 3.03 Impact Factor
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ABSTRACT: Protein kinase inhibitors are an important class of therapeutics. In addition, selective kinase inhibitors can often reveal unexpected biological insights, augmenting genetic approaches and playing a decisive role in preclinical target validation studies. Nevertheless, developing protein kinase inhibitors with sufficient selectivity and pharmacodynamic potency presents significant challenges. Targeting noncatalytic cysteines with covalent inhibitors is a powerful approach to address both challenges simultaneously. Here, we describe our efforts to design irreversible and reversible electrophilic inhibitors with varying degrees of kinase selectivity. Highly selective covalent inhibitors have been used to elucidate the roles of p90 ribosomal protein S6 kinases in animal models of atherosclerosis and diabetes. By contrast, semipromiscuous covalent inhibitors have revealed new therapeutic targets in disease-causing parasites and have shown utility as chemoproteomic probes for interrogating kinase occupancy in living cells.