Background:
Earlier diagnosis and advances in treatment strategies have increased the average survival of
cancer patients over the last decades. Despite the increased number of new anti-neoplastic agents, there has been no
adequate therapy for intricate malignancies such as pancreatic cancer. Cancer metabolism is the main building block
standing behind cancer promotion and progression even in the presence of a harsh environment. Targeting metabolic
pathways, such as glycolysis and pentose phosphate pathway, is regarded as a promising new strategy for cancer
treatment.
Objective:
The current study is to investigate the effect of knocking-down pancreatic cancer glycolytic and pentose
phosphate pathway's regulators (HIF-1α, ARNT, PFKFB4, and RBKS), on cell’s viability and resistance to gemcitabine
and doxorubicin, using small interference RNA.
Methodology:
The human pancreatic ductal adenocarcinoma cell line, Panc-1, was used to study the anti-proliferative
activity of targeting HIF-1α, ARNT, PFKFB4, and RBKS mRNAs by transfection with small interference RNAs, each
one alone and in combination. The transfected cells were also treated with doxorubicin and gemcitabine to study the
relationship between the concerned genes and the resistance of Panc-1 cells to these drugs. The effect on cell proliferation
was determined using a colorimetric assay and Inhibitory Concentration (IC50) calculation. A cross-talk study was done
to investigate the silencing effect of one of the above genes on the expression of others using Real Time-Polymerase
Chain Reaction.
Results:
In vitro transfection with small interference-RNAs, siHIF-1α, siPFKFB4, and siARNT decreased tumor cell
proliferation with a maximum effect shown with siPFKFB4; but there was no anti-proliferative effect with RBKS
silencing. suppression of transcription of HIF-1α, ARNT, PFKFB4, and RBKS sensitize pancreatic cancer cells, Panc-1,
to doxorubicin and gemcitabine.
Conclusion:
This study demonstrated the major tumor promoting and progressive effects of PFKFB4, while HIF-1α and
ARNT had modulator effects in pancreatic cancer cells (Panc-1). RBKS had a chemo-resistant role justifying its enhanced
expression in Panc-1 cells, but not a proliferative one. Silencing of all genes of interest decreased doxorubicin and gemcitabine's resistance and improved the antitumor effect of doxorubicin and gemcitabine in the pancreatic cancer cell
line, Panc-1.
HER-3 peptide vaccines/mimics: Combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells
