Evidence of galectin-1 involvement in glioma chemoresistance
Le Mercier M, Lefranc F, Mijatovic T, Debeir O, Haibe-Kains B, Bontempi G, Decaestecker C, Kiss R and Mathieu V
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) whose expression is stimulated by hypoxia is a potent
modulator of GBM cell migration and a pro-angiogenic molecule. Hypoxia
is also known to confer cancer cells with resistance to chemotherapy
and radiotherapy and to modulate the unfolded protein response (UPR)
during endoplasmic reticulum (ER) stress. The present study
investigates whether decreasing Gal1 expression (by means of a siRNA
approach) in human Hs683 GBM cells increases their sensitivity to
pro-autophagic or pro-apoptotic drugs. The data reveal that
temozolomide, the standard treatment for glioma patients, increases
Gal1 expression in Hs683 cells both in vitro and in vivo. However,
reducing Gal1 expression in these cells by siRNA increases the
anti-tumor effects of various chemotherapeutic agents, in particular
temozolomide both in vitro and in vivo. This decrease in Gal1
expression in Hs683 cells does not induce apoptotic or autophagic
features, but is found to modulate p53 transcriptional activity and
decrease p53-targeted gene expression including DDIT3/GADD153/ CHOP,
DUSP5 ATF3 and GADD45A. The decrease in Gal1 expression also impairs
the expression levels of seven other genes implicated in
chemoresistance: ORP150, HERP, GRP78/Bip, TRA1, BNIP3L, GADD45B and
CYR61, some of which are located in the ER and whose expression is also
known to be modified by hypoxia. This novel facet of Gal1 involvement
in glioblastoma biology may be amenable to therapeutic manipulation.