A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone antagonists.

MiR-629-5p Promotes Prostate Cancer Development and Metastasis by Targeting AKAP13

Prostate cancer (PCa) has become the most frequently occurring cancer among western men according to the latest report, and patients’ prognosis is often poor in the event of tumor progression, therefore, many researches are devoted to exploring the molecular mechanism of PCa metastasis. MicroRNAs (miRNA) have proved to play an important role in this process. In present study, by combining clinical samples with public databases, we found that miR-629-5p increased to varying degrees in primary localized PCa tissues and metastatic PCa tissues compared with adjacent normal tissues, and bioinformatics analysis suggested that high level of miR-629-5p was related to poor prognosis. Functionally, miR-629-5p drove PCa cell proliferation, migration and invasion in vitro, and promoted growth of PCa cells in vivo. Moreover, A-kinase Anchor Protein 13 (AKAP13) was screened as a direct target of miR-629-5p, that expression was negatively correlated with the malignant phenotype of tumor cells. In the end, through verification in clinical specimens, we found that AKAP13 could be independently used as a clinical prognostic indicator. Overall, the present study indicates that miR-629-5p plays an oncogenic role in PCa by targeting AKAP13, which provides a new idea for clinical diagnosis and treatment of complex refractory PCa.

Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC.

Common genetic alterations of SPOP-MATH domain in prostate cancer tissues and association with pathological tumor characteristic.

SPOP gene has a critical role in prostate cancer development and found high mutated in the prostate tumor through various populations. MATH domain represents an important site for SPOP-DNA linkage and other sensitive gene-gene interactions. To investigate the genetic alterations of the MATH domain of SPOP gene in prostate cancer biopsies and correlation with clinical and pathological parameters; DNA samples from 50 prostate cancer tissues were genotyped and confirmed by Sanger sequencing. The frequency and distribution of high frequent mutations were determined and correlated with the patients tumor characteristics. Among 50 samples 34 (68%) were carrying one or more common mutations. Novel frame shift deletion mutation: c.255delA (p.Leu86Phefs) was detected in eight patients (16%), in addition to five novel missense mutations with moderate frequency (6%) namely: c.209G>C (p.Arg70Pro), c.215A>C (p.Asn72Thr), c.334G>A (p.Glu112Lys), c.373T>C (p.Phe125Leu), and c.388G>A (p.Asp130Asn), All missense mutations located in MATH domain. The effects of novel mutations described in the MATH domain are uncertain. No significant differences between carriers and noncarriers of common mutations detected regarding Gleason score, prostate-specific antigen concentration PSA, and tumor stage [p > 0.05]. Clinical significance of mutations detected on prostate tumors progression can be investigated in future analysis. Our findings revealed novel SPOP alterations in prostate cancer tissues probably associated with cancer development.

Low Levels of Urinary PSA Better Identify Prostate Cancer Patients

Serum prostatic specific antigen (PSA) has proven to have limited accuracy in early diagnosis and in making clinical decisions about different therapies for prostate cancer (PCa). This is partially due to the fact that an increase in PSA in the blood is due to the compromised architecture of the prostate, which is only observed in advanced cancer. On the contrary, PSA observed in the urine (uPSA) reflects the quantity produced by the prostate, and therefore can give more information about the presence of disease. We enrolled 574 men scheduled for prostate biopsy at the urology clinic, and levels of uPSA were evaluated. uPSA levels resulted lower among subjects with PCa when compared to patients with negative biopsies. An indirect correlation was observed between uPSA amount and the stage of disease. Loss of expression of PSA appears as a characteristic of prostate cancer development and its evaluation in urine represents an interesting approach for the early detection of the disease and the stratification of patients.