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.