Galectin-1 regulates P53 and is implicated in glioma cell resistance to cytotoxic drugs

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

Purpose: Glioblastomas (GBMs) are resistant to apoptosis but less so to autophagy, a fact that may at least partly explain the therapeutic benefits of the pro-autophagic drug temozolomide in the treatment of GBM patients. Galectin-1 (Gal1) is a potent modulator of GBM cell migration and a pro-angiogenic molecule whose expression is stimulated by hypoxia. The present study investigates whether decreasing galectin-1 expression in human Hs683 GBM cells increases their sensitivity to pro-autophagic or pro-apoptotic drugs.

Experimental design: A siRNA approach was used to decrease Gal1 expression in Hs683 GBM cells. The effects of temozolomide and of pro-apoptotic drugs in this model in vitro and in vivo were studied. Additionally genome-wide microarray analysis was employed to identify chemoresistance-related genes.

Results: Temozolomide treatment increased Gal1 expression in Hs683 cells both in vitro and in vivo. Reducing Gal1 expression in these cells increased the anti-tumor effects of chemotherapeutical agents, in particular temozolomide both in vitro and in vivo. Decreasing Gal1 expression in Hs683 cells did not induce apoptotic or autophagic features, but decreased p53 transcriptional activity along with p53-targeted gene expression including DDIT3/GADD153/CHOP, DUSP5, ATF3 and GADD45A. The reduction in Gal1 expression also paralleled decreases in the expression levels of seven other genes implicated in chemoresistance: ORP150, HERP, Grp78/Bip, TRA1, BNIP3L, GADD45B and CYR61.

Conclusions: This novel facet of Gal1 involvement in the chemoresistance of GBM cells may be amenable to therapeutic manipulation.