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

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 b1 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.

Identification of Nidogen 1 as a lung metastasis protein through secretome analysis

“…Reminiscent of the role of TGFβ in cancer and metastatic progression, NID1 seems to be a tumor suppressor and metastasis promoter in our breast cancer and melanoma models. However, these functions may be cancer type-dependent, as NID1 promoted tumorigenesis and metastasis of endometrial cancer (Pedrola et al 2015), while loss of expression through promoter methylation in colon and gastric cancers (Ulazzi et al 2007) or increased protein degradation in prostate cancer (Ko et al 2015) correlated with enhanced tumor growth and metastasis. One possible mechanism by which NID1 may decrease tumorigenesis could be its strong binding affinity for perlecan, which can be secreted by quiescent ECs to mute proliferative and invasive phenotypes of lung and breast cancer cells in vitro and reduce their protumorigenic and proinflammatory signaling (Franses et al 2011).…”

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

“…Prominent TTSPs involved in PCa progression include matriptase‐1, matriptase‐2 and hepsin. Matriptase‐1 overexpression correlates with Gleason score (Riddick et al, 2005) promoting cell invasion, metastasis and prostate tumour growth (Sanders et al, 2006; Ko et al, 2015) by regulating MET signalling in PCa. Interestingly, matriptase‐1 interacts with a close relative of TMEFF2, TMEFF1, where the EGF‐like domain of TMEFF1 binds to the matriptase‐1 CUB domain (Ge et al, 2006).…”

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

“…TTSP-regulated proteolysis is a prerequisite for tissue homeostasis, however, uncontrolled expression and enhanced enzymatic activity of cell surface-attached TTSPs can lead to different disorders such as carcinogenesis 9 and contributes to influenza and other respiratory viral infections 10 . Moreover, TMPRSS2 accumulated in the glandular lumen of normal and cancerous prostate tissues can be proteolytically cleaved and the rise in released protease fragment levels can confirm the presence of cancer cells.…”

“…By use of the PAR-2 antagonist Phe-Ser-Leu-Leu-Arg-Tyr-NH 2 it was found that matriptase and TMPRSS2 can activate PAR2, which suggests an additional link between a membrane-anchored serine protease and prostate tumor metastasis. However, further studies should be conducted if excessive amount of TMPRSS2 in intracellular space may play a functional role in prostate tumorigenesis in addition to cell surface protease activity 9,13,19 .…”