Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand‐independent manner via Plexin B1. SEMA3C expression levels increase in castration‐resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide‐resistant progression. Plexin B1 sema domain‐containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post‐castration in vivo. SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

Purpose: GLI transcription factors mediate hedgehog signaling and have been implicated in several human malignancies, including prostate cancer. The objectives of this study were to characterize GLI2 expression levels in human prostate cancer cell lines and tissues to test the effect of antisense oligonucleotide (ASO) targeting GLI2 on androgen-independent (AI) prostate cancer cell lines. Experimental Design: A tissue microarray was used to characterize differences in GLI2 expression in benign prostate hyperplasia, prostate cancer treated by neoadjuvant hormonal therapy and AI prostate cancer. The effects of GLI2 ASO on PC-3 cell growth and paclitaxel chemosensitivity were assessed in vitro and in vivo. Oligonucleotide spotted microarray analysis was used to determine alteration in GLI2 coregulated genes after ASO treatment. Results: The expression of GLI2 was significantly higher in prostate cancer than in benign prostate hyperplasia, decreased after androgen ablation in a time-dependent fashion, but became highly expressed again in AI prostate cancer. GLI2 ASO treatment of PC-3 cells reduced GLI2 mRNA and protein levels in a dose-dependent manner. GLI2 knockdown increased PC-3 cell apoptotic rates and significantly decreased cell growth and modulated levels of apoptosis-related genes, such as Bcl2, Bcl-xL, and clusterin. GLI2 knockdown also changed levels of several cell cycle regulators, such as cyclin D1, p27, and PKC-D. Systematic administration of GLI2 ASO in athymic mice significantly delayed PC-3 tumor progression and enhanced paclitaxel chemosensitivity. Conclusions: These findings suggest that increased levels of GLI2 correlates with AI progression and that GLI2 may be a therapeutic target in castrate-resistant prostate cancer.

Using high molecular-weight proteomic analysis, we previously showed that Staphylococcal nuclease domain-containing protein 1 (SND1) is highly expressed in recurrent androgen-insensitive prostate cancer tissues. SND1 is a component of the RNA-induced splicing complex that mediates RNA interference, leading to degradation of specific mRNAs. The objective of this study was to further characterize SND1 expression and to investigate its biological potential in prostate cancer. Radical prostatectomy specimens were obtained from 62 prostate cancer patients. SND1 immunohistochemical staining patterns were evaluated using an in-house polyclonal antibody. We confirmed SND1 mRNA expression in prostate cancer cells using an in situ hybridization technique. To determine the importance of SND1 mRNA, we knocked down SND1 in vitro with small interfering RNA and observed a significant decrease in cell growth. SND1 was expressed in 60 of 62 prostate cancers (97%), appearing in the cytoplasm as small, granular structures; it was also present at high levels in prostate cancer specimens, while in hyperplasia specimens and normal epithelium, it was weakly or negatively expressed. SND1 expression intensity increased with increasing grade and aggressiveness of the cancer. As SND1 mRNA was overexpressed in cancer cells, the growth of these cells was suppressed following SND1 knockdown in vitro, thus representing a promising prostate cancer biomarker and therapeutic target.

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Renin-angiotensin system inhibition can reverse age-related, advanced cardiac hypertrophy. The mechanism of reversal is partly due to suppression of cardiac oxidative stress.