Molecular Validation of PACE4 as a Target in Prostate Cancer

Abstract

Prostate cancer remains the single most prevalent cancer in men. Standard therapies are still limited and include androgen ablation that initially causes tumor regression. However, tumor cells eventually relapse and develop into a hormone-refractory prostate cancer. One of the current challenges in this disease is to define new therapeutic targets, which have been virtually unchanged in the past 30 years. Recent studies have suggested that the family of enzymes known as the proprotein convertases (PCs) is involved in various types of cancers and their progression. The present study examined PC expression in prostate cancer and validates one PC, namely PACE4, as a target. The evidence includes the observed high expression of PACE4 in all different clinical stages of human prostate tumor tissues. Gene silencing studies targeting PACE4 in the DU145 prostate cancer cell line produced cells (cell line 4-2) with slower proliferation rates, reduced clonogenic activity, and inability to grow as xenografts in nude mice. Gene expression and proteomic profiling of the 4-2 cell line reveals an increased expression of known cancer-related genes (e.g., GJA1, CD44, IGFBP6) that are downregulated in prostate cancer. Similarly, cancer genes whose expression is decreased in the 4-2 cell line were upregulated in prostate cancer (e.g., MUC1, IL6). The direct role of PACE4 in prostate cancer is most likely through the upregulated processing of growth factors or through the aberrant processing of growth factors leading to sustained cancer progression, suggesting that PACE4 holds a central role in prostate cancer.

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

“…The overexpression of PACE4 in prostate cancer has been documented; however, no correlations with clinical parameters, such as Gleason grading, have been reported (6,13,14). New molecular markers with relevance to prostate cancer progression should show a positive correlation with the established histologic prognostic indicator, that is, Gleason grading, to be considered of prognostic usefulness.…”

“…In prostate cancer, among other PCs, PACE4 is specifically overexpressed and carries nonredundant growth-sustaining functions for cancer cells (6,7). PACE4 inhibition using either silencing tools or the high affinity PACE4 inhibitor: [dL]LLLRVK-amidinobenzylamide (Amba) herein called C23, both prevented prostate cancer tumor progression (8).…”

Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion

“…The reverse transcription and quantitative PCR procedure was described previously (37). ProSAAS primers were described previously (38).…”

Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target

“…Whereas these studies mostly examined overexpression of PACE4, our present study focused on gene silencing as a predictive approach to define potential therapeutic benefits, as we have also recently demonstrated with prostate cancer [7], [11], [15]. The role of PACE4 in ovarian homeostasis has already been documented [34], and its expression has also been shown to be decreased in ovarian cancer tissues [9].…”