Down-regulation of topoisomerase II alpha is caused by up-regulation of GRP78.
Glucose-regulated protein of M(r) 78kDa (GRP78) is a resident protein of endoplasmic reticulum (ER). We have previously shown that the cells become resistant to topoisomerase II alpha (topo II alpha) targeted cancer chemotherapeutic drug such as etoposide (VP-16) when GRP78 is up-regulated by various means. Up-regulation of GRP78 in V79 Chinese hamster cell lines was achieved by treating the cells with NAD antagonist 6-aminonicotinamide (6AN), inhibitor of glucose metabolism such as 2-deoxyglucose (2dG). Further, up-regulation of GRP78 was also observed in V79-derived cell lines which are deficient in poly(ADP-ribose) polymerase (PARP1) metabolism. However, mechanisms of association of GRP78 up-regulation and resistance to VP-16 remained obscured under the conditions outlined above. In the manuscript, using various methods, we demonstrate, for the first time, that up-regulation of GRP78, using approaches depicted above, causes down-regulation of topo II alpha and its activity. We have also discussed the clinical implications of our findings.
Gosky
David
D
Hematology/Oncology Division, Department of Medicine, Cancer Research Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
Chatterjee
Satadal
S
D015120:6-Aminonicotinamide / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis*; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation; D004351:Drug Resistance; D000091342:Endoplasmic Reticulum Chaperone BiP; D005047:Etoposide / Q000494:pharmacology; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones / Q000096:biosynthesis*; D011506:Proteins / Q000378:metabolism; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; D015120:6-Aminonicotinamide; D005047:Etoposide; D004247:DNA; D003847:Deoxyglucose; D004250:DNA Topoisomerases, Type II