title: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Ko
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Pai
authors.initials: CP
authors.lastname: Juan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shao-Wei
authors.initials: SW
authors.lastname: Lan
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. Bureau of Investigation, Ministry of Justice, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Shyu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shang-Ru
authors.initials: SR
authors.lastname: Wu
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Department and Graduate Institute of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. mslee2006@ntu.edu.tw.
authors.forename: Ming-Shyue
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000728:Androgens; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; C485595:matriptase