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
(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
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.