Matriptase is involved in ErbB-2-induced prostate cancer cell invasion.
Deregulation of both ErbB-2 signaling and matriptase activity has been associated with human prostate cancer (PCa) progression. In this communication, we investigated the roles of both ErbB-2 signaling in matriptase zymogen activation and matriptase in ErbB-2-induced PCa malignancy. In a human PCa cell progression model, we observed that advanced PCa C-81 LNCaP cells exhibited an aggressive phenotype with increased cell migration and invasion capacity; these cells concurrently showed both enhanced ErbB-2 phosphorylation and increased matriptase zymogen activation compared with parental C-33 LNCaP cells. Moreover, ErbB2 activation, both ligand-dependent (eg, epidermal growth factor treatment) and ligand-independent (eg, overexpression), was able to induce matriptase zymogen activation in this cell line. Inhibition of ErbB-2 activity by either the specific inhibitor, AG825, in epidermal growth factor-treated C-33 LNCaP cells or ErbB-2 knockdown in C-81 LNCaP cells, reduced matriptase activation. These observations were confirmed by similar studies using both DU145 and PC3 cells. Together, these data suggest that ErbB-2 signaling plays an important role in matriptase zymogen activation. ErbB-2-enhanced matriptase activation was suppressed by a phosphatidylinositol 3-kinase inhibitor (ie, LY294002) but not by a MEK inhibitor (ie, PD98059). Suppression of matriptase expression by small hairpin RNA knockdown in ErbB-2-overexpressing LNCaP cells dramatically suppressed cancer cell invasion. In summary, our data indicate that ErbB-2 signaling via the phosphatidylinositol 3-kinase pathway results in up-regulated matriptase zymogen activity, which contributes to PCa cell invasion.
Wu
Shang-Ru
SR
Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, R817, 8F, No. 1, Section 1, Jen-Ai Rd, Taipei, Taiwan.
Cheng
Tai-Shan
TS
Chen
Wen-Chi
WC
Shyu
Hsin-Yi
HY
Ko
Chun-Jung
CJ
Huang
Hsiang-Po
HP
Teng
Chen-Hsin
CH
Lin
Chia-Hau
CH
Johnson
Michael D
MD
Lin
Chen-Yong
CY
Lee
Ming-Shyue
MS
D000728:Androgens / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D055785:Gene Knockdown Techniques; D018734:Genes, erbB-2 / Q000502:physiology*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000728:Androgens; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D012697:Serine Endopeptidases; C508053:ERBB2 protein, human; C485596:ST14 protein, human