TMPRSS2, a Serine Protease Expressed in the Prostate on the Apical Surface of Luminal Epithelial Cells and Released into Semen in Prostasomes, Is Misregulated in Prostate Cancer Cells

Abstract

TMPRSS2, a type II transmembrane serine protease, is highly expressed by the epithelium of the human prostate gland. To explore the regulation and function of TMPRSS2 in the prostate, a panel of monoclonal antibodies with high sensitivity and specificity were generated. Immunodetection showed TMPRSS2 on the apical plasma membrane of the prostate luminal cells and demonstrated its release into semen as a component of prostasomes, organelle-like vesicles that may facilitate sperm function and enhance male reproduction. In prostate cancer cells, TMPRSS2 expression was increased and the protein mislocalized over the entire tumor cell membrane. In both LNCaP prostate cancer cells and human semen, TMPRSS2 protein was detected predominantly as inactive zymogen forms as part of an array of multiple noncovalent and disulfide-linked complexes, suggesting that TM-PRSS2 activity may be regulated by unconventional mechanisms. Our data suggested that TMPRSS2, an apical surface serine protease, may have a normal role in male reproduction as a component of prostasomes.The aberrant cellular localization, and increased expression of the protease seen in cancer, may contribute to prostate tumorigenesis by providing access of the enzyme to nonphysiological substrates and binding

Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis

“…In this study, our data suggest that androgen signaling exhibits an induction effect on prostate cancer cell invasion via upregulation of its target gene TMPRSS2. In prostate cancer, the expression level of TMPRSS2 has shown a significant increase in malignant cancer tissues compared with benign tissues (18,30), whereas TMPRSS2 expression level in metastatic cancer tissues is not significantly different from that in benign prostatic tissues (18). Our data also indicate that the protein level of TMPRSS2 is significantly increased in moderately and intermediately differentiated prostate cancer tissues (GS5-6&7) compared with normal prostate tissues.…”

“…Recent studies have indicated that a gene fusion of the 5 0 untranslational region of TMPRSS2 to E26 transformation-specific (ETS) transcription factors (ERG and ETV1) is often observed in prostate cancer tissues (16). In addition, TMPRSS2 protein level has been shown to be correlated with prostate cancer progression (17,18). However, the in vivo substrates of TMPRSS2 and the TMPRSS2-initiated proteolytic cascade are unknown, and the exact role of TMPRSS2 in prostate cancer progression is still unclear.…”

Matriptase Expression and Zymogen Activation in Human Pilosebaceous Unit

“…Immunohistochemical staining was performed as previously described (Chen et al, 2011;Chen et al, 2010a). Tissue sections of frozen human skin were fixed with formalin and stained using the total matriptase mAb M32 and/ or M24, activated matriptase mAb M69, or HAI-1 mAb M19, and followed by the secondary antibody (EnVision+ Dual Link System Peroxidase) (Dako, Glostrup, Denmark).…”

Matriptase and prostasin are expressed in human skin in an inverse trend over the course of differentiation and are targeted to different regions of the plasma membrane

“…Immunohistochemical staining was performed as previously described (Chen et al, 2011, 2010a). Tissue sections of frozen human skin were fixed with formalin and stained using the total matriptase mAb M32, activated matriptase mAb M69, prostasin mAb YL11, HAI-1 mAb M19, or mouse IgG as negative control, followed by the secondary antibody (EnVision+ Dual Link System Peroxidase) (Dako, Glostrup, Denmark).…”