Cellular
prion protein (PrP(C)), a
copper-binding
glycosyl-phosphatidylinositol (GPI)-anchored
membrane protein that is expressed predominantly in neurons can be induced in
ischemia/hypoxic brain tissues. It was also found to be overexpressed and conferred multidrug resistance, promoting
cancer metastasis and inhibiting apoptosis in
gastric cancer in our lab. In solid
tumors,
hypoxia can promote malignant progression and confer resistance to
chemotherapy by altering gene expression. In present study, we investigated the molecular mechanisms and signaling pathway involved in the induction of the PrP(C) gene by
hypoxia in
cancer cell lines. PrP(C) was detected to be upregulated in several
cancer cell lines at both
mRNA and
protein level, and then found to be induced by
hypoxia in a time-dependent manner. After
hypoxia treatment,
gastric cancer MKN28 cells transfected with
luciferase reporter constructs of the human PrP(C) promoter, which contained HSE, expressed higher
luciferase activities (4.3-fold) than those cells transfected with the constructs containing no HSE. In addition, the upregulation of PrP(C) was reduced by MERK/ERK inhibitor (
PD98059).
siRNA knockdown of PrP(C) could make the cells more sensitive to
hypoxia induced drug sensitivity. In conclusion, from these findings, we can propose that some transcriptional factors phosphorylated by ERK1/2, could in turn interact with HSE in the promoter of PrP(C) resulting in upregulation of PrP(C) in
gastric cancer cell line MKN28 during
hypoxia. Downregulation of PrP(C) makes
gastric cancer cells more sensitive to
hypoxia induced drug sensitivity. However, other mechanisms might also be responsible for
hypoxia induced overexpression of PrP(C) in
gastric cancer.