Wnt Signaling In Prostate Cancer Research Articles

Novel biomarkers and drug correlations of non-canonical WNT signaling in prostate and breast cancer

Prostate cancer (PCa) and breast cancer (BC) present formidable challenges in global cancer-related mortality, necessitating effective management strategies. The present study explores non-canonical Wnt signaling in PCa and BC, aiming to identify biomarkers and assess their clinical and therapeutic implications. Co-expression analyses reveal distinct gene patterns, with five overlapping genes (SULF1, ALG3, IL16, PLXNA2 and RASGFR2) exhibiting divergent expression in both cancers. Clinical relevance investigations demonstrate correlations with TNM stages and biochemical recurrence. Drug correlation analyses unveil potential therapeutic avenues, indicating that Wnt5a and ROR2 expressions are related to MEK inhibitor sensitivity in cancers. Meanwhile, further correlation analyses were conducted between drugs and the other novel non-canonical WNT genes (ALG3, IL16, SULF1, PLXNA2, and RASGRF2). Our findings contribute to understanding non-canonical Wnt signaling, offering insights into cancer progression and potential personalized treatment approaches.

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer.

Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance.

Dickkopf2promotes proliferation and invasion via Wnt signaling in prostate cancer.

Wnt/β-catenin signaling dysregulation is involved in tumorigenesis. Furthermore, epigenetic modification of the Dickkopf (DKK) family (DKK1‑4) has been shown to be important in the regulation of Wnt signaling. However, the functions and mechanism of DKK2in the development and progression of prostate cancer remain unclear. Therefore, the present study investigated the role of DKK2in prostate cancer. The mRNA and protein expression levels of DKK2in prostate cancer tissues and cells were assessed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The biological function of DKK2in prostate cancer was investigated using 3‑(4,5‑dimethylthiazol‑2‑yl)-2,5‑diphenyltetrazolium bromide and transwell invasion assays. DKK2was demonstrated to be upregulated in prostate cancer tissues and cells, and knockdown of DKK2suppressed cell proliferation and invasion. Furthermore, small interfering RNA targeting DKK2inhibited the expression of β‑catenin, cyclinD1and c‑Myc in prostate cancer cells. The present report suggested that DKK2downregulation suppressed the proliferation and invasion of prostate cancer cells by inhibiting the Wnt/β‑catenin signaling pathway.

ERG Is a Critical Regulator of Wnt/LEF1 Signaling in Prostate Cancer

Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG upregulation in approximately 50% of prostate cancers. Studies to date have shown important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. Here, we report that ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms. ERG bound to the promoters of various Wnt genes to directly increase ligand expression. Consequently, ERG overexpression increased active β-catenin level in the cells and enhanced TCF/LEF1 luciferase reporter activity, which could be partially blocked by WNT-3A inhibitor IWP-2. Most importantly, our data defined LEF1 as a direct target of ERG and that LEF1 inhibition fully abolished ERG-induced Wnt signaling and target gene expression. Furthermore, functional assays showed that Wnt/LEF1 activation phenocopied that of ERG in inducing cell growth, epithelial-to-mesenchymal transition, and cell invasion, whereas blockade of Wnt signaling attenuated these effects. Concordantly, LEF1 expression is significantly upregulated in ERG-high human prostate cancers. Overall, this study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis. Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer.

Abstract 4937: KIF3A promotes prostate cancer cell proliferation, migration, and invasion via activation of Dvl2 and the Wnt signaling pathway.

Abstract Aberrant activation of the Wnt signaling pathway is a key event in advanced prostate cancer. However, the mutations in APC complex that activate Wnt signaling in many other cancers are rare in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be elucidated. Here we show that KIF3A, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3A is up-regulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3A correlate with higher Gleason score, TNM grade, and metastatic status of prostate cancer. Moreover, overexpression of KIF3A stimulates the benign p69 prostate cell growth, whereas depletion of KIF3A by shRNA suppresses LNCaP cell proliferation, anchorage-independent growth, and cell migration/invasion. Mechanistically, we demonstrate that KIF3A activates DVL2 and induces transcriptional activation of Cyclin D1, HEF1, and MMP9 in prostate cancer cell lines that are required for cancer cell proliferation, migration, and invasion. Taking together, these findings indicate that KIF3A is a potent agonist of Wnt signaling in prostate cancer and suggest that up-regulation of KIF3A is causal of aberrant activation of Wnt signaling in advanced prostate cancer. Inactivation of KIF3A may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated. Citation Format: Zun Liu, Ryan E. Rebowe, Zemin Wang, Zehua Wang, John S. DePaolo, Jianhui Guo, Yingchun Li, Chiping Qian, Wanguo Liu. KIF3A promotes prostate cancer cell proliferation, migration, and invasion via activation of Dvl2 and the Wnt signaling pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4937. doi:10.1158/1538-7445.AM2013-4937

The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition

BackgroundAberrations in the Wnt pathway have been reported to be involved in the metastasis of prostate cancer (PCa) to bone. We investigated the effect and underlying mechanism of a naturally-occurring Wnt inhibitor, WIF1, on the growth and cellular invasiveness of a bone metastatic PCa cell line, PC3.ResultsThe WIF1 gene promoter was hypermethylated and its expression down-regulated in the majority (7 of 8) of PCa cell lines. Restoration of WIF1 expression in PC-3 cells resulted in a decreased cell motility and invasiveness via up-regulation of epithelial markers (E-cadherin, Keratin-8 and-18), down-regulation of mesenchymal markers (N-cadherin, Fibronectin and Vimentin) and decreased activity of MMP-2 and -9. PC3 cells transfected with WIF1 consistently demonstrated reduced expression of Epithelial-to-Mesenchymal Transition (EMT) transcription factors, Slug and Twist, and a change in morphology from mesenchymal to epithelial. Moreover, WIF1 expression significantly reduced tumor growth by approximately 63% in a xenograft mouse model. This was accompanied by an increased expression of E-cadherin and Keratin-18 and a decreased expression of vimentin in tumor tissues.ConclusionThese data suggest that WIF1 regulates tumor invasion through EMT process and thus, may play an important role in controlling metastatic disease in PCa patients. Blocking Wnt signaling in PCa by WIF1 may represent a novel strategy in the future to reduce metastatic disease burden in PCa patients.

A Novel Role for Wnt/Ca2+ Signaling in Actin Cytoskeleton Remodeling and Cell Motility in Prostate Cancer

Wnt signaling is a critical regulatory pathway in development and disease. Very little is known about the mechanisms of Wnt signaling in prostate cancer, a leading cause of death in men. A quantitative analysis of the expression of Wnt5A protein in human tissue arrays, containing 600 prostate tissue cores, showed >50% increase in malignant compared to benign cores (p<0.0001). In a matched pair of prostate cancer and normal cell line, expression of Wnt5A protein was also increased. Calcium waves were induced in prostate cells in response to Wnt5A with a 3 fold increase in Flou-4 intensity. The activity of Ca2+/calmodulin dependent protein kinase (CaMKII), a transducer of the non-canonical Wnt/Ca2+ signaling, increased by 8 fold in cancer cells; no change was observed in β-catenin expression, known to activate the canonical Wnt/β-catenin pathway. Mining of publicly available human prostate cancer oligoarray datasets revealed that the expression of numerous genes (e.g., CCND1, CD44) under the control of β-catenin transcription is down-regulated. Confocal and quantitative electron microscopy showed that specific inhibition of CaMKII in cancer cells causes remodeling of the actin cytoskeleton, irregular wound edges and loose intercellular architecture and a 6 and 8 fold increase in the frequency and length of filopodia, respectively. Conversely, untreated normal prostate cells showed an irregular wound edge and loose intercellular architecture; incubation of normal prostate cells with recombinant Wnt5A protein induced actin remodeling with a regular wound edge and increased wound healing capacity. Live cell imaging showed that a functional consequence of CaMKII inhibition was 80% decrease in wound healing capacity and reduced cell motility in cancer cells. We propose that non-canonical Wnt/Ca2+ signaling via CaMKII acts as a novel regulator of structural plasticity and cell motility in prostate cancer.

WT1 and Wnt Signaling in Prostate Cancer.

WT1 and Wnt Signaling in Prostate Cancer.