Vascular Targeting and Antiangiogenesis Agents Induce Drug Resistance Effector GRP78 within the Tumor Microenvironment
- 1 July 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (13) , 5785-5791
- https://doi.org/10.1158/0008-5472.can-05-0754
Abstract
Therapeutic targeting of the tumor vasculature that destroys preexisting blood vessels of the tumor and antiangiogenesis therapy capitalize on the requirement of tumor cells on an intact vascular supply for oxygen and nutrients for growth, expansion and metastasis to the distal organs. Whereas these classes of agents show promise in delaying tumor progression, they also create glucose and oxygen deprivation conditions within the tumor that could trigger unintended prosurvival responses. The glucose-regulated protein GRP78, a major endoplasmic reticulum chaperone, is inducible by severe glucose depletion, anoxia, and acidosis. Here we report that in a xenograft model of human breast cancer, treatment with the vascular targeting agent, combretastatin A4P, or the antiangiogenic agent, contortrostatin, promotes transcriptional activation of the Grp78 promoter and elevation of GRP78 protein in surviving tumor cells. We further show that GRP78 is overexpressed in a panel of human breast cancer cells that has developed resistance to a variety of drug treatment regimens. Suppression of GRP78 through the use of lentiviral vector expressing small interfering RNA sensitizes human breast cancer cells to etoposide-mediated cell death. Our studies imply that antivascular and antiangiogenesis therapy that results in severe glucose and oxygen deprivation will induce GRP78 expression that could lead to drug resistance.Keywords
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This publication has 41 references indexed in Scilit:
- Spontaneous and Controllable Activation of Suicide Gene Expression Driven by the Stress-InducibleGrp78Promoter Resulting in Eradication of Sizable Human TumorsHuman Gene Therapy, 2004
- Induction of Grp78/BiP by Translational BlockJournal of Biological Chemistry, 2003
- Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosisThe Journal of cell biology, 2003
- BAX and BAK Regulation of Endoplasmic Reticulum Ca 2+ : A Control Point for ApoptosisScience, 2003
- Hypoxia promotes invasive growth by transcriptional activation of the met protooncogeneCancer Cell, 2003
- Glucose Deprivation Induces Heme Oxygenase-1 Gene Expression by a Pathway Independent of the Unfolded Protein ResponsePublished by Elsevier ,2002
- Hypoxia — a key regulatory factor in tumour growthNature Reviews Cancer, 2002
- Coupling Endoplasmic Reticulum Stress to the Cell Death ProgramJournal of Biological Chemistry, 2001
- Increased cytotoxicity of chronic hypoxic cells by molecular inhibition of GRP78 inductionInternational Journal of Radiation Oncology*Biology*Physics, 1994
- Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cellsTrends in Biochemical Sciences, 1987