Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. Our previous study revealed that hypoxia-inducible factor-1 (HIF-1), the major transcriptional factor significantly activated by hypoxia, was overexpressed in gastric vincristine-resistant cells SGC7901/vincristine (VCR) under normoxic conditions, which suggested that it was associated with drug resistance in gastric cancer cells. In the present study, a colonyforming assay revealed that hypoxia and forced HIF-1α α α α expression increased maximal -8.9-fold or -14.8-fold of IC 50 toward vincristine in gastric cancer cell lines SGC7901 and SGC7901/VCR, respectively (P < 0.01). Annexin-V/propidium iodide staining analysis revealed hypoxia or forced HIF-1α α α α expression reduced apoptosis by 24% or 18% in SGC7901 cells (P < 0.05). Flow cytometry analysis of intracellular adriamycin revealed that hypoxia and forced expression of HIF-1α α α α increased -1.79-fold or -2.36-fold of the adriamycin releasing index, respectively (P < 0.05). However, resistance acquisition subject to hypoxia in vitro and H ypoxia, frequently found in the center of solid tumors, is a major obstacle in the development of effective cancer chemotherapy.(1,2) It was reported that hypoxia decreased the efficacy of cisplatin, etoposide, bleomycin, and mitomycin C in testicular germ cell tumors, (3) and the colorectal cancer cell line maintained anti-apoptotic potential under hypoxia. In pancreatic cancer cells, hypoxia increases resistance to apoptosis induced by gemcitabine.(4) Growing evidence suggests that hypoxia in tumors selects for cells with decreased potential for apoptosis through the overexpression of Bcl-2 and decreased killing effect through upregulation of drug transporter protein, (5,6) may contribute to resistance to standard radiation therapy and chemotherapy. (7)(8)(9)

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI) -anchored membrane protein that is highly conserved in mammalian species. PrPc has the characteristics of adhesive molecules and is thought to play a role in cell adhesion and membrane signaling. Here we investigated the possible role of PrPc in the process of invasiveness and metastasis in gastric cancers. PrPc was found to be highly expressed in metastatic gastric cancers compared to nonmetastatic ones by immunohistochemical staining. PrPc significantly promoted the adhesive, invasive, and in vivo metastatic abilities of gastric cancer cell lines SGC7901 and MKN45. PrPc also increased promoter activity and the expression of MMP11 by activating phosphorylated ErK1/2 in gastric cancer cells. MEK inhibitor PD98059 and MMP11 antibody (Ab) significantly inhibited in vitro invasive and in vivo metastatic abilities induced by PrPc. N-terminal fragment (amino acid 24-90) was suggested to be an indispensable region for signal transduction and invasion-promoting function of PrPc. Taken together, the present work revealed a novel function of PrPc that the existence of N-terminal region of PrPc could promote the invasive and metastatic abilities of gastric cancer cells at least partially through activation of MEK/ERK pathway and consequent transactivation of MMP11.

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