Decreasing galectin-1 expression in human experimental glioblastomas impairs the endoplasmic reticulum stress (ERS) response and increases temozolomide anti-tumor effects.

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 1967 Malignant gliomas, and especially glioblastomas (GBMs) are characterized by the diffuse invasion of distant brain tissue by a myriad of single migrating cells with reduced levels of apoptosis (Type I programmed cell death (PCD)), and consequent resistance to the cytotoxic insults of pro-apoptotic drugs (Lefranc et al., J Clin Oncol 2005). In contrast, GBM cells display sensitivity to autophagy, i.e. Type II PCD (Kanzawa et al., Cell Death Differ 2004), a fact that can at least partly explain the therapeutic benefits of the pro-autophagic drug temozolomide in the treatment of GBM patients. Galectin-1 plays a number of vital roles in Ras signaling, which in turn is pivotal to GBM development and resistance to apoptosis (see Camby et al., Glycobiology, 2006, for review). The stable inhibition of galectin-1 expression in human U87 GBM cells alters the expression of a number of genes that either directly or indirectly influences the adhesion, the motility and the invasive ability of human glioblastoma cells, and additionally, immunocompromized mice intracranially grafted with human GBM cells constitutively expressing low levels of galectin-1 had longer survival periods than mice grafted with GBM cells expressing normal levels of galectin-1 (see Camby et al., Glycobiology, 2006, for review). The data in the present study reveal that treating Hs683 human GBM cells with temozolomide increases galectin-1 expression, suggesting therefore a cytoprotective role for galectin-1. Reducing galectin-1 expression in human Hs683 GBM cells using a specifically designed anti-galectin-1 siRNA does not induce apoptotic or autophagic features. In contrast, this galectin-1 depletion decreases the levels of expression of several genes involved in the response to endoplasmic reticulum stress; including DUSP5, HERP, DNAJB9/MDG1/ERdj4 and HYOU1/ORP150, the latter of which modulates angiogenesis via the processing of VEGF. Reduced galectin-1 expression in Hs683 tumor cells also leads to sustained decreases in VEGF expression, with severe in vivo impairment of angiogenesis in Hs683 orthotopic xenografts. Furthermore, the in vivo delivery of a non-viral infusion of anti-galectin-1 siRNA into the ventricular system of the brains of adult mice orthotopically grafted with Hs683 GBM cells increases the anti-tumor effects of temozolomide. This novel facet of galectin-1 involvement in glioblastoma biology may be amenable to therapeutic manipulation.