ORP150, a major target of Galectin-1 pro-angiogenic effects in human Hs683 glioblastoma xenografts

Lefranc F, Le Mercier M, Mathieu V, Haibe-Kains B, Bontempi G, Mijatovic T, Decaestecker C, Kiss R

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. In contrast, GBM cells display sensitivity to autophagy, i.e. Type II PCD, 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 (Gal1) is a hypoxia-regulated pro-angiogenic factor that directly participates in GBM cell migration processes. The stable inhibition of Gal1 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. Additionally, immunocompromized mice intracranially grafted with human GBM cells constitutively expressing low levels of Gal1 had longer survival periods than mice grafted with GBM cells expressing normal levels of Gal1.
The present data show that Gal1 exerts its pro-angiogenic effects in human Hs683 experimental GBMs through an IRE1alpha-mediated control of the expression of ORP150 that controls in turn VEGF maturation. Gal1 also modulates the expression of 7 other hypoxia related genes implicated in angiogenesis (CTGF, ATF3, PPP1R15A, HSPA5, TRA1 and CYR61). In addition, decreasing Gal1 expression in Hs683 orthotopic xenografts induces marked endoplasmic reticulum stress, which in turn leads to an improvement of the therapeutic benefits contributed by the pro-autophagic drug temozolomide.