Glucose-related protein (GRP78) and its relationship to the drug-resistance proteins P170, GST-pi, LRP56 and angiogenesis in non-small cell lung carcinomas.
Several studies have documented that induction of the glucose-related protein (GRP78) is associated with the development of drug-resistance to antitumor drugs. However, nothing has been reported concerning GRP78 in human lung tumors and its relationship to several resistance proteins and angiogenesis. Therefore, this study analyzed the expression of GRP78 in a series of 62 consecutive lung cancer patients and examined whether or not a relationship exists between GRP78, several resistance proteins and microvessel density (MVD). Secondary, it evaluated the relationship of GRP78, LRP56 and GST-pi in cancer cell lines under hypoxic conditions and in sensitive and resistant cell lines. We determined that a relationship exists between GRP78 and the resistance proteins P170, LRP56 and GST-pi in human lung cancer. Furthermore, we observed an up-regulation of GRP78 in the resistant cell lines LUTC-ML54, OAW-Dox and OAW-Tax, but not in sensitive cell lines. Abnormal vascularization of malignant tumors is associated with the development of hypoxic regions. In hypoxic regions, several proteins, including drug resistance proteins, are expressed in greater quantities. Our study detected an inverse correlation between GRP78 and MVD. Carcinomas with low MVD exhibited a higher expression of GRP78. Furthermore, protein expression of GRP78, GST-pi and LRP56 increased in the cell lines A-549, RPMI-2650 and SC-MES-1 under hypoxic conditions. These observations suggest that hypoxia, tumor vascularization and the simultaneous expression of many resistance-related proteins, including GRP78, may play an important role in drug response and therapeutic effectiveness.
Koomägi
R
R
Department of Oncological Diagnostics and Therapy, German Cancer Research Center, Heidelberg, Germany.
Mattern
J
J
Volm
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006360:Heat-Shock Proteins; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D018832:Molecular Chaperones / Q000096:biosynthesis*; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C117055:HTI56 protein, human; D006360:Heat-Shock Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D018832:Molecular Chaperones; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase