Protein kinase D1 inhibits cell proliferation through matrix metalloproteinase-2 and matrix metalloproteinase-9 secretion in prostate cancer.
We and others previously showed that protein kinase D1 (PKD1) is downregulated in several cancers including prostate; interacts with E-cadherin, a major cell adhesion epithelial protein; and causes increased cell aggregation and decreased motility of prostate cancer cells. In this study, we show that PKD1 complexes with beta3-integrin, resulting in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-ERK pathway, which causes increased production of matrix metalloproteinase (MMP)-2 and MMP-9, that is associated with shedding of soluble 80 kDa E-cadherin extracellular domain. Interestingly, decreased cell proliferation following PKD1 transfection was rescued by MMP-2 and MMP-9 inhibitors and augmented by recombinant MMP-2 (rMMP-2) and rMMP-9 proteins, suggesting an antiproliferative role for MMPs in prostate cancer. Translational studies by in silico analysis of publicly available DNA microarray data sets show a significant direct correlation between PKD1 and MMP-2 expression in human prostate tissues. The study shows a novel mechanism for antiproliferative effects of PKD1, a protein of emerging translational interest in several human cancers, through increased production of MMP-2 and MMP-9 in cancer cells.
Division of Urology, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
M Helal Uddin
MH
Biswas
Cheng
C
Du
Chuanyou
C
Zhang
Juerg
J
Straubhaar
Lucia R
LR
Languino
K C
KC
Balaji
D015820:Cadherins / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D015820:Cadherins; D039661:Integrin beta3; D061965:Matrix Metalloproteinase Inhibitors; C089212:protein kinase D; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9