Abstract
Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. ©2017 AACR.
Highlights
Among malignancies, prostate cancer remains the most common type of cancer in men, with 233,000 new cases each year in the United States, representing 27% of all new cancer cases, as well as the second most common cause of cancer-related mortality [1]
Using matched cancerous and adjacent noncancerous tissues (ANCT), PACE4 mRNA levels were analyzed by real-time quantitative PCR
IHC analyses of specimens from different tumor grades with an antibody targeting the catalytic domain of PACE4 corroborated our results as once again overexpression was visible with increasing levels in higher grade foci (Fig. 1C)
Summary
Prostate cancer remains the most common type of cancer in men, with 233,000 new cases each year in the United States, representing 27% of all new cancer cases, as well as the second most common cause of cancer-related mortality [1]. When diagnosed in its early progression stages, clinical interventions are able to circumvent disease progression and yield high survival rates over 5–15 years. If tumor initiated metastatic dissemination, as occurring at the time of diagnosis or following recurrence, survival rates drop considerably, leading to patient death within 5 years in approximately 75% of cases. The treatment for metastatic prostate cancer involves androgen suppression therapy but remains palliative. Once resistance to castration occurs, the only option remaining is chemotherapy. Novel targeted therapeutic avenues arising from yet unexplored biological pathways may provide a solution, either alone or as cotargets
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