PMID- 22797919
OWN - NLM
STAT- MEDLINE
DCOM- 20130529
LR  - 20211021
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Print)
IS  - 0021-9533 (Linking)
VI  - 125
IP  - Pt 20
DP  - 2012 Oct 15
TI  - PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-kappaB- and 
      HDAC1-mediated expression and activation of uPA.
PG  - 4800-11
LID - 10.1242/jcs.106542 [doi]
AB  - Although protein kinase D3 (PKD3) has been shown to contribute to prostate cancer 
      cell growth and survival, the role of PKD in prostate cancer cell motility 
      remains unclear. Here, we show that PKD2 and PKD3 promote nuclear factor kappa B 
      (NF-kappaB) signaling and urokinase-type plasminogen activator (uPA) 
      expression/activation, which are crucial for prostate cancer cell invasion. 
      Silencing of endogenous PKD2 and/or PKD3 markedly decreased prostate cancer cell 
      migration and invasion, reduced uPA and uPA receptor (uPAR) expression and 
      increased plasminogen activator inhibitor-2 (PAI-2) expression. These results 
      were further substantiated by the finding that PKD2 and PKD3 promoted the 
      activity of uPA and matrix metalloproteinase 9 (MMP9). Furthermore, depletion of 
      PKD2 and/or PKD3 decreased the level of binding of the p65 subunit of NF-kappaB to 
      the promoter of the gene encoding uPA (PLAU), suppressing transcriptional 
      activation of uPA. Endogenous PKD2 and PKD3 interacted with inhibitor of NF-kappaB 
      (IkappaB) kinase beta (IKKbeta); PKD2 mainly regulated the phosphorylated IKK 
      (pIKK)-phosphorylated IkappaB (pIkappaB)-IkappaB degradation cascade, p65 nuclear 
      translocation, and phosphorylation of Ser276 on p65, whereas PKD3 was responsible 
      for the phosphorylation of Ser536 on p65. Conversely, inhibition of uPA 
      transactivation by PKD3 silencing was rescued by constitutive Ser536 p65 
      phosphorylation, and reduced tumor cell invasion resulting from PKD2 or PKD3 
      silencing was rescued by ectopic expression of p65. Interestingly, PKD3 
      interacted with histone deacetylase 1 (HDAC1), suppressing HDAC1 expression and 
      decreasing its binding to the uPA promoter. Moreover, depletion of HDAC1 resulted 
      in recovery of uPA transactivation in PKD3-knockdown cells. Taken together, these 
      data suggest that PKD2 and PKD3 coordinate to promote prostate cancer cell 
      invasion through p65 NF-kappaB- and HDAC1-mediated expression and activation of uPA.
FAU - Zou, Zhipeng
AU  - Zou Z
AD  - Department of Cell Biology, School of Basic Medical Sciences, Southern Medical 
      University, Guangzhou, China.
FAU - Zeng, Fangyin
AU  - Zeng F
FAU - Xu, Wanfu
AU  - Xu W
FAU - Wang, Chunxia
AU  - Wang C
FAU - Ke, Zhiyong
AU  - Ke Z
FAU - Wang, Q Jane
AU  - Wang QJ
FAU - Deng, Fan
AU  - Deng F
LA  - eng
GR  - R01 CA129127/CA/NCI NIH HHS/United States
GR  - R01 CA142580/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120713
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (TRPP Cation Channels)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (polycystic kidney disease 2 protein)
RN  - EC 2.7.1.- (protein kinase C nu)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - EC 3.4.24.35 (MMP9 protein, human)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.5.1.98 (HDAC1 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylase 1)
SB  - IM
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - *Histone Deacetylase 1/genetics/metabolism
MH  - Humans
MH  - Male
MH  - Matrix Metalloproteinase 9/genetics/metabolism
MH  - Neoplasm Invasiveness
MH  - Phosphorylation
MH  - Prostatic Neoplasms/genetics/metabolism
MH  - *Protein Kinase C/genetics/metabolism
MH  - Signal Transduction
MH  - *TRPP Cation Channels/genetics/metabolism
MH  - *Transcription Factor RelA/genetics/metabolism
MH  - Transcriptional Activation/genetics
MH  - *Urokinase-Type Plasminogen Activator/genetics/metabolism
PMC - PMC4074284
EDAT- 2012/07/17 06:00
MHDA- 2013/05/31 06:00
PMCR- 2013/10/15
CRDT- 2012/07/17 06:00
PHST- 2012/07/17 06:00 [entrez]
PHST- 2012/07/17 06:00 [pubmed]
PHST- 2013/05/31 06:00 [medline]
PHST- 2013/10/15 00:00 [pmc-release]
AID - jcs.106542 [pii]
AID - 10.1242/jcs.106542 [doi]
PST - ppublish
SO  - J Cell Sci. 2012 Oct 15;125(Pt 20):4800-11. doi: 10.1242/jcs.106542. Epub 2012 
      Jul 13.