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.
Highlights
The tumor vasculature provides a new and attractive target for cancer therapy because of the reliance of most tumor cells on an intact vascular supply for their growth and survival [1]
Our studies further reveal that this induction occurs only in the tumor microenvironment, but not in tissue culture, suggesting that the destruction of the tumor vasculature by combretastatin A4P (CA4P) and contortrostatin could be a shared mechanism for Grp78 induction
Using a MDA-MB435 cell line stably transduced with G1NaGrpTK, we investigate whether CA4P activates the Grp78 promoter within the tumor microenvironment by following the kinetics of induction of the HSVTK expression upon CA4P treatment
Summary
The tumor vasculature provides a new and attractive target for cancer therapy because of the reliance of most tumor cells on an intact vascular supply for their growth and survival [1]. This concept is based on the premise that normal endothelial cells may be more amendable to therapeutic intervention than tumor cells, many of which harbor adaptive mutations rendering them insensitive to anticancer drugs [2]. This selectivity depends on a short in vivo exposure of the drug and on its rapidly reversible effects on the cytoskeleton
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have