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Evidence of galectin-1 involvement in glioma chemoresistance
Marie Le Mercier1, Florence Lefranc, Tatjana Mijatovic
1Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium.
Abstract:
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.
Insights
Reducing Galectin-1 (Gal1) expression in glioblastoma (GBM) cells enhances sensitivity to chemotherapy, including temozolomide. This approach modulates p53 activity and chemoresistance genes, offering a new therapeutic strategy for GBM treatment.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastomas (GBMs) exhibit resistance to apoptosis but are sensitive to autophagy, influencing temozolomide efficacy.
- Galectin-1 (Gal1), upregulated by hypoxia, promotes GBM cell migration and angiogenesis.
- Hypoxia contributes to chemoresistance and radiotherapy resistance in cancer cells by modulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress.
Purpose of the Study:
- To investigate if reducing Galectin-1 (Gal1) expression in human Hs683 GBM cells enhances their sensitivity to pro-autophagic or pro-apoptotic drugs.
- To explore the molecular mechanisms underlying the effect of Gal1 modulation on GBM chemoresistance.
Main Methods:
- Utilized a siRNA approach to decrease Galectin-1 (Gal1) expression in human Hs683 GBM cells.
- Assessed the impact of Gal1 reduction on cellular sensitivity to chemotherapeutic agents, including temozolomide, both in vitro and in vivo.
- Analyzed changes in p53 transcriptional activity and the expression of p53-targeted genes and other chemoresistance-associated genes.
Main Results:
- Temozolomide treatment increased Galectin-1 (Gal1) expression in Hs683 GBM cells.
- Reducing Gal1 expression via siRNA significantly enhanced the anti-tumor effects of chemotherapeutic agents, notably temozolomide, in vitro and in vivo.
- Decreased Gal1 expression modulated p53 transcriptional activity, reduced expression of p53-targeted genes (e.g., DDIT3/CHOP, ATF3, GADD45A), and impaired expression of other chemoresistance genes (e.g., ORP150, GRP78/Bip).
Conclusions:
- Galectin-1 (Gal1) plays a crucial role in glioblastoma chemoresistance.
- Reducing Gal1 expression represents a potential therapeutic strategy to overcome chemoresistance in GBM.
- The findings highlight a novel mechanism involving Gal1, p53 modulation, and ER-stress-related genes in GBM chemoresistance.
