Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C1855645 (
KPC
)
1,473
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Purpose
: Pancreatic ductal adenocarcinoma (PDAC) is a malignant disease with a poor prognosis. One prominent aspect of PDAC that contributes to its aggressive behavior is its altered cellular metabolism. The aim of this study was to characterize the oncogenic effects of ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, in PDAC development and to assess its potential as a therapeutic target for PDAC.
Experimental Design
: The expression of UQCRC1 in human PDAC tissues and p48-Cre/p53Flox/WT/LSL-KrasG12D (
KPC
) mouse pancreatic intraepithelial neoplasias (PanINs) was determined by immunohistochemistry. The role of UQCRC1 in promoting PDAC growth was evaluated
in vitro
in PANC-1 and CFPAC-1 cells and
in vivo
in transplanted mouse models of PDAC. Extracellular flux and RNA-Seq analyses were applied to investigate the mechanism of UQCRC1 in the regulation of mitochondrial metabolism and PDAC cell growth. The therapeutic potential of UQCRC1 in PDAC was assessed by knockdown of UQCRC1 using an RNA interference approach.
Results
: UQCRC1 expression showed a gradual increase during the progression from PanIN stages to PDAC in
KPC
mice. Elevated expression of UQCRC1 was observed in 72.3% of PDAC cases and was correlated with poor prognosis of the disease. UQCRC1 promoted PDAC cell growth in both
in vitro
experiments and
in vivo
subcutaneous and orthotopic mouse models. UQCRC1 overexpression resulted in increased mitochondrial oxidative phosphorylation (OXPHOS) and
ATP
production. The overproduced
ATP
was released into the extracellular space via the pannexin 1 channel and then functioned as an autocrine or paracrine agent to promote cell proliferation through the
ATP
/P2Y2-RTK/AKT axis. UQCRC1 knockdown or
ATP
release blockage could effectively inhibit PDAC growth.
Conclusion
: UQCRC1 has a protumor function and may serve as a potential prognostic marker and therapeutic target for PDAC.
...
PMID:Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. 3208 37
Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (
LSL-Kras
G12D/+
;
LSL-Trp53
R172H/+
;
Pdx-1-Cre
mice;
KPC
mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in
KPC
mice.
In vitro
assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of
ATP
. Dinaciclib treatment inhibited proliferation and induced apoptosis in
KPC
tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8
+
T cells were increased after dinaciclib treatment in
KPC
mice. Additionally, the mean apparent diffusion coefficient values of
KPC
tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in
KPC
mice.
...
PMID:Dinaciclib prolongs survival in the
LSL-Kras
G12D/+
;
LSL-Trp53
R172H/+
;
Pdx-1-Cre
(KPC) transgenic murine models of pancreatic ductal adenocarcinoma. 3226 32
