PMID- 23144866
OWN - NLM
STAT- MEDLINE
DCOM- 20130425
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 11
DP  - 2012
TI  - Targeting COX-2/PGE(2) pathway in HIPK2 knockdown cancer cells: impact on 
      dendritic cell maturation.
PG  - e48342
LID - 10.1371/journal.pone.0048342 [doi]
LID - e48342
AB  - BACKGROUND: Homeodomain-interacting protein kinase 2 (HIPK2) is a multifunctional 
      protein that exploits its kinase activity to modulate key molecular pathways in 
      cancer to restrain tumor growth and induce response to therapies. For instance, 
      HIPK2 knockdown induces upregulation of oncogenic hypoxia-inducible factor-1 
      (HIF-1) activity leading to a constitutive hypoxic and angiogenic phenotype with 
      increased tumor growth in vivo. HIPK2 inhibition, therefore, releases pathways 
      leading to production of pro-inflammatory molecules such as vascular endothelial 
      growth factor (VEGF) or prostaglandin E2 (PGE(2)). Tumor-produced inflammatory 
      mediators other than promote tumour growth and vascular development may permit 
      evasion of anti-tumour immune responses. Thus, dendritic cells (DCs) dysfunction 
      induced by tumor-produced molecules, may allow tumor cells to escape 
      immunosurveillance. Here we evaluated the molecular mechanism of PGE(2) 
      production after HIPK2 depletion and how to modulate it. METHODOLOGY/PRINCIPAL 
      FINDINGS: We show that HIPK2 knockdown in colon cancer cells resulted in 
      cyclooxygenase-2 (COX-2) upregulation and COX-2-derived PGE(2) generation. At 
      molecular level, COX-2 upregulation depended on HIF-1 activity. We previously 
      reported that zinc treatment inhibits HIF-1 activity. Here, zinc supplementation 
      to HIPK2 depleted cells inhibited HIF-1-induced COX-2 expression and PGE(2)/VEGF 
      production. At translational level, while conditioned media of both siRNA control 
      and HIPK2 depleted cells inhibited DCs maturation, conditioned media of only 
      zinc-treated HIPK2 depleted cells efficiently restored DCs maturation, seen as 
      the expression of co-stimulatory molecules CD80 and CD86, cytokine IL-10 release, 
      and STAT3 phosphorylation. CONCLUSION/SIGNIFICANCE: THESE FINDINGS SHOW THAT: 1) 
      HIPK2 knockdown induced COX-2 upregulation, mostly depending on HIF-1 activity; 
      2) zinc treatment downregulated HIF-1-induced COX-2 and inhibited PGE(2)/VEGF 
      production; and 3) zinc treatment of HIPK2 depleted cells restored DCs 
      maturation.
FAU - Garufi, Alessia
AU  - Garufi A
AD  - Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina 
      Elena National Cancer Institute, Rome, Italy.
FAU - Pistritto, Giuseppa
AU  - Pistritto G
FAU - Ceci, Claudia
AU  - Ceci C
FAU - Di Renzo, Livia
AU  - Di Renzo L
FAU - Santarelli, Roberta
AU  - Santarelli R
FAU - Faggioni, Alberto
AU  - Faggioni A
FAU - Cirone, Mara
AU  - Cirone M
FAU - D'Orazi, Gabriella
AU  - D'Orazi G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121107
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Carrier Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.14.99.1 (PTGS2 protein, human)
RN  - EC 2.7.1.- (HIPK2 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - J41CSQ7QDS (Zinc)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Carrier Proteins/*genetics/metabolism
MH  - *Cell Differentiation
MH  - Cell Line, Tumor
MH  - Cyclooxygenase 2/genetics/*metabolism
MH  - Dendritic Cells/*physiology
MH  - Dinoprostone/genetics/*metabolism
MH  - Down-Regulation/drug effects
MH  - Gene Expression
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/physiology
MH  - Protein Serine-Threonine Kinases/*genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/drug effects
MH  - Tumor Escape
MH  - Vascular Endothelial Growth Factor A/genetics/metabolism
MH  - Zinc/pharmacology
PMC - PMC3492329
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/11/13 06:00
MHDA- 2013/04/26 06:00
PMCR- 2012/11/07
CRDT- 2012/11/13 06:00
PHST- 2012/06/15 00:00 [received]
PHST- 2012/09/24 00:00 [accepted]
PHST- 2012/11/13 06:00 [entrez]
PHST- 2012/11/13 06:00 [pubmed]
PHST- 2013/04/26 06:00 [medline]
PHST- 2012/11/07 00:00 [pmc-release]
AID - PONE-D-12-17399 [pii]
AID - 10.1371/journal.pone.0048342 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(11):e48342. doi: 10.1371/journal.pone.0048342. Epub 2012 Nov 7.