GRK3 is essential for metastatic cells and promotes prostate tumor progression (original) (raw)
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GRK2 enforces androgen receptor dependence in the prostate and prostate tumors
Oncogene, 2020
Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces ARdependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression towards the deadliest stage. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Distinct expression and activity of GSK‐3α and GSK‐3β in prostate cancer
International Journal of Cancer, 2012
Glycogen synthase kinase (GSK‐3) is upregulated in many types of tumor, including prostate cancer. GSK‐3 inhibitors reduce prostate tumor cell growth; however, it is not clear if both isoforms, GSK‐3α and GSK‐3β, are involved. Here, we compared their expression in prostate tumors and used gene silencing to study their functions in 22Rv1 prostate cancer cells. Compared to normal prostate, GSK‐3α and GSK‐3β were upregulated in 25/79 and 24/79 cases of prostate cancer, respectively, with GSK‐3α elevated in low Gleason sum score tumors and GSK‐3β expressed in high Gleason tumors, and both isoforms correlating with high expression of the androgen receptor (AR). Gene silencing of GSK‐3α and, to a lesser extent, GSK‐3β reduced AR transcriptional activity. In addition, silencing of GSK‐3β, but not GSK‐3α, reduced Akt phosphorylation. Acute and chronic silencing of either isoform reduced 22Rv1 growth in colony formation assays; however, this did not correlate with effects on AR activity. The...
G-Protein–Coupled Receptor Kinase 2 as a Potential Modulator of the Hallmarks of Cancer
Molecular Pharmacology, 2016
Malignant features-such as sustained proliferation, refractoriness to growth suppressors, resistance to cell death or aberrant motility, and metastasis-can be triggered by a variety of mutations and signaling adaptations. Signaling nodes can act as cancer-associated factors by cooperating with oncogenegoverned pathways or participating in compensatory transduction networks to strengthen tumor properties. G-protein-coupled receptor kinase 2 (GRK2) is arising as one of such nodes. Via its complex network of connections with other cellular proteins, GRK2 contributes to the modulation of basic cellular functionssuch as cell proliferation, survival, or motility-and is involved in metabolic homeostasis, inflammation, or angiogenic processes. Moreover, altered GRK2 levels are starting to be reported in different tumoral contexts and shown to promote breast tumorigenesis or to trigger the tumoral angiogenic switch. The ability to modulate several of the hallmarks of cancer puts forward GRK2 as an oncomodifier, able to modulate carcinogenesis in a cell-type specific way.
HGK promotes metastatic dissemination in prostate cancer
Scientific Reports
Metastasis is the process of cancer cell dissemination from primary tumors to different organs being the bone the preferred site for metastatic homing of prostate cancer (PCa) cells. Prostate tumorigenesis is a multi-stage process that ultimately tends to advance to become metastatic PCa. Once PCa patients develop skeletal metastases, they eventually succumb to the disease. Therefore, it is imperative to identify essential molecular drivers of this process to develop new therapeutic alternatives for the treatment of this devastating disease. Here, we have identified MAP4K4 as a relevant gene for metastasis in PCa. Our work shows that genetic deletion of MAP4K4 or pharmacological inhibition of its encoded kinase, HGK, inhibits metastatic PCa cells migration and clonogenic properties. Hence, MAP4K4 might promote metastasis and tumor growth. Mechanistically, our results indicate that HGK depleted cells exhibit profound differences in F-actin organization, increasing cell spreading and ...
Suppression of glycogen synthase kinase 3 activity reduces tumor growth of prostate cancer in vivo
The Prostate, 2011
BACKGROUND. Glycogen synthase kinase 3 (GSK-3) has been regarded as a potential therapeutic target for multiple human cancers. We previously reported that suppression of GSK-3 activity with lithium chloride (LiCl) or small chemical inhibitors impaired cellular DNA synthesis and reduced cell proliferation in prostate cancer cells. Therefore, in this study, we extended this in vitro findings to in vivo settings in order to establish a proof of concept that inhibition of GSK-3 activity is feasible in suppressing tumor growth of prostate cancer in vivo. METHODS. In this study, we used three GSK-3 inhibitors, LiCl, TDZD-8, and L803-mts, which are structurally unrelated and non-ATP competitive. Human prostate cancer cell lines PC-3 and C4-2 were used for nude mouse xenograft models. The autochthonous transgenic prostate cancer TRAMP mice were used for testing GSK-3 inhibitor's effect on tumor development. Anti-Ki-67 and BrdU immunohistochemistry was used to determine cell proliferation. The pE2F-TA-LUC (E2F-LUC) luciferase reporter assay and gene specific small interferencing RNA technique were used to examine C/EBP involvement in GSK-3 inhibitor-induced E2F-1 suppression. RESULTS. Using mouse xenograft models, we demonstrated that LiCl and TDZD-8 significantly suppressed tumor development and growth of subcutaneous xenografts derived from human prostate cancer cells. Similarly, in the TRAMP mice, TDZD-8 and L803-mts reduced the incidence and tumor burden in the prostate lobes. Consistent with our previous in vitro findings, GSK-3 inhibitors significantly reduced BrdU incorporation and Ki67-positive cells in xenograft tumors and mouse cancerous prostates compared to the control. Further analysis revealed that following GSK-3 inhibition, C/EBPa, a negative cell cycle regulator, was remarkably accumulated in xenograft tumors or in cultured prostate cancer cells. Meanwhile, knocking down C/EBPa expression abolished GSK-3 inhibition-induced suppression of E2F1 transactivation, suggesting that C/EBPa accumulation is involved in GSK-3 inhibition-induced anti-tumor effect. CONCLUSION. Taken together, these results suggest that GSK-3 inhibition has the potential as a therapeutic strategy for prostate cancer intervention, although further pre-clinical and clinical testing are desirable. Prostate 71: 835-845, 2011. #
Expression of G protein-coupled receptor kinase 4 is associated with breast cancer tumourigenesis
The Journal of Pathology, 2008
G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-bound, activated, G-protein-coupled receptors (GPCRs). GRKs and β-arrestins are key participants in the canonical pathways leading to phosphorylation-dependent GPCR desensitization, endocytosis, intracellular trafficking and resensitization. Here we show that GRK4 isoforms are expressed in human breast cancer but not in normal epithelia. In addition, GRK4-overexpressing cells activated the mitogen-activated protein kinase (MAPK) mediated by ERK 1/2 and JNK phosphorylation in breast cancer-derived cell lines. Furthermore, suppression of β-arrestins decreased GRK4-stimulated ERK 1/2 or JNK phosphorylations. These data indicate that high-level expression of GRK4 may activate MAPK signalling pathways mediated by β-arrestins in breast cancer cells, suggesting that GRK4 may be implicated in breast cancer carcinogenesis.
Anticancer research, 2009
Activation of glycogen synthase kinase-3 (GSK-3) is involved in the regulation of cell growth, differentiation, mobility, proliferation and survival. However, its clinicopathologic significance remains unclear in prostate cancer (PCa). A tissue microarray was produced from 640 samples. Sections were immunostained with an antibody against the non-phosphorylated form of GSK-3(GSK-3beta) and were digitized. Spearman correlation test was processed for correlations between GSK-3beta and biological and clinicopathological variables. The prognostic value of GSK-3beta was analyzed by Cox Regression model. Cytoplasmic GSK-3beta was higher in PCa than in normal prostate (mean expression index 4.55 vs. 3.50, p<0.0001). Conversely, nuclear expression was higher in normal prostate than that in PCa (3.38 vs. 2.04, p<0.0001). Cytoplasmic levels of GSK-3beta were correlated with clinical stage (rho=0.095, p=0.0337), lymph node metastasis (rho=0.116, p=0.0096), extracapsular extension (rho=0.0...
Molecular Endocrinology, 2014
Both androgen and phosphatidylinositol 3-kinase (PI3K) signaling are critical for cell proliferation of androgen receptor (AR)-positive prostate cancer cells, but the underlying mechanisms are still not fully understood. Here we report that serum-and glucocorticoid-inducible kinase 3 (SGK3), a Ser/Thr kinase functioning downstream of PI3K, is an AR transcriptional target and promotes prostate cancer cell proliferation. SGK3 expression is up-regulated by androgen DHT via AR. We identified an AR-binding region at the sgk3 locus, which confers androgen responsiveness of sgk3 promoters. Interestingly, we found that androgen/AR-dependent SGK3 expression requires estrogen receptor (ER) (including both isoforms, ER␣ and ER). Depletion of ER blocked DHT-induced SGK3 expression. Functionally, knockdown of SGK3 expression significantly decreased LNCaP prostate cancer cell proliferation by inhibiting G 1 to S phase cell cycle progression. We further provided evidence that SGK3 promotes p70 S6 kinase (p70S6K) activation and increases cyclin D1 levels. In summary, our study identifies SGK3 as an AR target and provides a novel androgeninduced cell proliferation mechanism mediated by the AR-SGK3-p70S6K-cyclin D1 pathway in prostate cancer cells.
Oncogene, 2004
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is b-catenin. Interest in the role of b-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of b-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous b-catenin on AR activity using Axin and RNA interference. Axin, which promotes b-catenin degradation, inhibited AR transcriptional activity. However, this did not require the b-catenin-binding domain of Axin. Depletion of b-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous b-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.
Cancer Research, 2014
G protein-coupled receptor kinases (GRKs) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced directed cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer.