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.