The hedgehog/Gli signaling paradigm in prostate cancer

Abstract

Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog's influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone.

Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

“…Previously, aberrant HH signaling in prostate tumors was reported to be ligand-dependent, although it is controversial whether this is in a paracrine or autocrine manner (3). In fact, the HH pathway is part of a complex signaling network that remains incompletely understood (9).…”

“…In spite of early detection techniques and multidisciplinary therapeutic approaches, the overall 5-year survival rate remains <30% in China (2). Anti-androgen treatment remains the first-line therapy for patients with prostate cancer, among whom the majority will eventually develop highly metastatic androgen-independent prostate cancer (3). Prostate cancer is a complex and heterogeneous disease characterized by various molecular signatures in patients, which provides opportunities to explore targeted therapies.…”

“…Ectopic activation of the Hedgehog (HH) signaling pathway has been demonstrated to be involved in the initiation as well as the progression of prostate malignancy (3,6). The HH signaling pathway was first identified in Drosophila as a central organizer for proper embryonic patterning and development.…”

Contemporary approaches to prostate cancer research

“…Foreword the IL-6/AR interaction, which is both stimulatory and inhibitory to prostate cancer cells [5]; and the interaction between Gli proteins and AR, which implicates hedgehog and androgen signaling pathways [6]. The role of androgens in epithelial-mesenchymal transition and mesenchymal-epithelial transition provide further need to block androgen action and metastatic spread [7].…”

Role of GLI-1 in epidermal growth factor-induced invasiveness of ARCaPE prostate cancer cells

“…Furthermore, EGFR expression increases during progression to a hormone-resistant stage (15)(16)(17). Previous studies have demonstrated that epidermal growth factor (EGF) signaling and Hedgehog (HH) signaling are both involved in prostate cancer tumorigenesis and progression (18)(19)(20)(21)(22)(23); however, whether there is any 'crosstalk' between these two important pathways requires clarification. In the present study, we mainly explored the role of GLI-1, which is the transcription factor of HH signaling, in EGF-regulated enhancement of the invasiveness of ARCaP E prostate cancer cells in vitro.…”