Abstract
Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin β1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer.
Highlights
Prostate cancer is the most frequent male malignancy and a leading cause of cancer-related death in many Western countries [1]
To analyze the effect of androgens on prostate cancer cell motility, androgen-sensitive LNCaP cells were used for cell migration and invasion assays because the cells are the most representative model for studying androgen signaling in prostate cancer cells [20]
The results showed that DHT significantly induced the expression of TMPRSS2 but not the other membrane-anchored serine proteases (MASP), and that the induction of TMPRSS2 was antagonized by bicalutamide, a similar induction phenomenon as seen in the well-known androgen-regulated gene, PSA (Supplementary Fig. S1B and S1C)
Summary
Prostate cancer is the most frequent male malignancy and a leading cause of cancer-related death in many Western countries [1]. Androgen signaling generally regulates the expression of genes associated with cancer cell growth and survival [2]. Because androgen signaling has been shown to be involved in prostate cancer development and progression [3], androgen deprivation therapy is an option for the patients. Most prostate cancer cells respond to this therapy, but eventually tumors relapse and take on a castration therapy– resistant prostate cancer phenotype that correlates with poor prognosis and high metastatic potential [4]. Androgen signaling has been shown to be involved in prostate cancer cell. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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