Osteopontin upregulates the expression of glucose transporters in osteosarcoma cells
Journal
PLoS ONE
Journal Volume
9
Journal Issue
10
Pages
e109550
Date Issued
2014
Author(s)
Abstract
Osteosarcoma is the most common primary malignancy of bone. Even after the traditional standard surgical therapy, metastasis still occurs in a high percentage of patients. Glucose is an important source of metabolic energy for tumor proliferation and survival. Tumors usually overexpress glucose transporters, especially hypoxia-responsive glucose transporter 1 and glucose transporter 3. Osteopontin, hypoxia-responsive glucose transporter 1, and glucose transporter 3 are overexpressed in many types of tumors and have been linked to tumorigenesis and metastasis. In this study, we investigated the regulation of glucose transporters by osteopontin in osteosarcoma. We observed that both glucose transporters and osteopontin were upregulated in hypoxic human osteosarcoma cells. Endogenously released osteopontin regulated the expression of glucose transporter 1 and glucose transporter 3 in osteosarcoma and enhanced glucose uptake into cells via the αvβ3 integrin. Knockdown of osteopontin induced cell death in 20% of osteosarcoma cells. Phloretin, a glucose transporter inhibitor, also caused cell death by treatment alone. The phloretin-induced cell death was significantly enhanced in osteopontin knockdown osteosarcoma cells. Combination of a low dose of phloretin and chemotherapeutic drugs, such as daunomycin, 5-Fu, etoposide, and methotrexate, exhibited synergistic cytotoxic effects in three osteosarcoma cell lines. Inhibition of glucose transporters markedly potentiated the apoptotic sensitivity of chemotherapeutic drugs in osteosarcoma. These results indicate that the combination of a low dose of a glucose transporter inhibitor with cytotoxic drugs may be beneficial for treating osteosarcoma patients. ? 2014 Hsieh et al.
SDGs
Other Subjects
daunorubicin; etoposide; fluorouracil; glucose; glucose transporter; glucose transporter 1; glucose transporter 2; glucose transporter 3; methotrexate; mitogen activated protein kinase p38; osteopontin; phloretin; phosphatidylinositol 3 kinase; stress activated protein kinase; vitronectin receptor; agents affecting water, molecule or ion transport; antineoplastic agent; daunorubicin; etoposide; fluorouracil; glucose transporter; glucose transporter 1; glucose transporter 3; methotrexate; osteopontin; phloretin; SLC2A1 protein, human; SLC2A3 protein, human; vitronectin receptor; apoptosis; Article; cancer growth; cell death; cell survival; cell viability; concentration response; controlled study; cytotoxicity; down regulation; flow cytometry; glucose transport; human; human cell; hypoxia; osteosarcoma cell; protein expression; protein function; signal transduction; upregulation; antagonists and inhibitors; bone tumor; metabolism; osteosarcoma; tumor cell line; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Daunorubicin; Etoposide; Fluorouracil; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 1; Glucose Transporter Type 3; Humans; Integrin alphaVbeta3; Membrane Transport Modulators; Methotrexate; Osteopontin; Osteosarcoma; Phloretin; Up-Regulation
Type
journal article