The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas.
Poor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. GRP78 is a key regulator of the unfolded protein response (UPR). As a Ca2+-binding molecular chaperone in the endoplasmic reticulum (ER), GRP78 maintains ER homeostasis, suppresses stress-induced apoptosis, and controls UPR signaling. We report here that GRP78 is expressed at low levels in normal adult brain, but is significantly elevated in malignant glioma specimens and human malignant glioma cell lines, correlating with their rate of proliferation. Down-regulation of GRP78 by small interfering RNA leads to a slowdown in glioma cell growth. Our studies further reveal that temozolomide, the chemotherapeutic agent of choice for treatment of malignant gliomas, leads to induction of CHOP, a major proapoptotic arm of the UPR. Knockdown of GRP78 in glioblastoma cell lines induces CHOP and activates caspase-7 in temozolomide-treated cells. Colony survival assays further establish that knockdown of GRP78 lowers resistance of glioma cells to temozolomide, and, conversely, overexpression of GRP78 confers higher resistance. Knockdown of GRP78 also sensitizes glioma cells to 5-fluorouracil and CPT-11. Treatment of glioma cells with (-)-epigallocatechin gallate, which targets the ATP-binding domain of GRP78 and blocks its protective function, sensitizes glioma cells to temozolomide. These results identify a novel chemoresistance mechanism in malignant gliomas and show that combination of drugs capable of suppressing GRP78 with conventional agents such as temozolomide might represent a novel approach to eliminate residual tumor cells after surgery and increase the effectiveness of malignant glioma chemotherapy.
Pyrko
Peter
P
Department of Pathology, and University of Southern California/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
Schönthal
Axel H
AH
Hofman
Florence M
FM
Chen
Thomas C
TC
Lee
Amy S
AS
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D053179:Caspase 7 / Q000378:metabolism; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000077204:Temozolomide; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014162:Transfection
C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D000077146:Irinotecan; D003606:Dacarbazine; D002392:Catechin; C045651:epigallocatechin gallate; D053179:Caspase 7; D005472:Fluorouracil; D002166:Camptothecin; D000077204:Temozolomide