Hypoxia induced overexpression of PrP(C) in gastric cancer cell lines.
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.
Liang
Jie
J
State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Bai
Feihu
F
Luo
Guanhong
G
Wang
Jingbo
J
Liu
Jingmei
J
Ge
Fulin
F
Pan
Yanglin
Y
Yao
Liping
L
Du
Rui
R
Li
Xiaohua
X
Fan
Rui
R
Zhang
Hongbo
H
Guo
Xuegang
X
Wu
Kaichun
K
Fan
Daiming
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013274:Stomach Neoplasms / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018621:PrPC Proteins; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases