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Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model
Véronique Mathieu1, Marie Le Mercier, Nancy De Neve
1Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium.
Abstract:
The rapid increase in the incidence of malignant melanomas has not been associated with improved therapeutic options over the years. Indeed melanomas have proven resistant to apoptosis (type I programmed cell death (PCD)) and consequently to most chemotherapy and immunotherapy. It is believed that this resistance can be partly overcome by proautophagic drugs inducing type II (autophagy) PCD. Change at the genomic, transcriptional, and post-translational level of G-proteins and protein kinases, including Ras, plays an important role in the ability of melanomas to resist apoptosis. Ras transformation itself requires membrane anchorage and the overexpression of galectin-1 increases membrane-associated Ras. In this study, it has been found that decreasing galectin-1 expression in B16F10 mouse melanoma cells in vitro by means of an anti-galectin-1 small interfering RNA approach does not modify their sensitivity to type I and type II PCD. However, it does induce heat shock protein 70-mediated lysosomal membrane permeabilization, a process associated with cathepsin B release into the cytosol, which in turn is believed to sensitize the cells to the proautophagic effects of temozolomide when grafted in vivo. Furthermore, temozolomide when compared to the proapoptotic drug cisplatin, significantly increased the survival times of mice in the B16F10 melanoma model.
Insights
This study shows that targeting galectin-1 in melanoma cells enhances their sensitivity to autophagy-inducing drugs. Temozolomide, an autophagy drug, significantly improved survival in a mouse melanoma model compared to cisplatin.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Pathways
Background:
- Malignant melanomas exhibit resistance to apoptosis (Type I programmed cell death), limiting chemotherapy and immunotherapy efficacy.
- This resistance is linked to alterations in G-proteins and protein kinases, such as Ras, and galectin-1 overexpression.
- Autophagy (Type II programmed cell death) is a potential strategy to overcome apoptosis resistance in melanoma.
Purpose of the Study:
- To investigate the role of galectin-1 in melanoma apoptosis resistance.
- To evaluate the effect of decreasing galectin-1 on melanoma cell sensitivity to Type I and Type II programmed cell death (PCD).
- To assess the therapeutic potential of temozolomide in a melanoma model with modified galectin-1 expression.
Main Methods:
- Utilized an anti-galectin-1 small interfering RNA approach to reduce galectin-1 expression in B16F10 mouse melanoma cells in vitro.
- Assessed sensitivity to Type I and Type II PCD.
- Induced lysosomal membrane permeabilization via heat shock protein 70.
- Evaluated the in vivo efficacy of temozolomide versus cisplatin in a B16F10 melanoma mouse model.
Main Results:
- Decreasing galectin-1 expression did not alter sensitivity to Type I or Type II PCD.
- Reduced galectin-1 induced heat shock protein 70-mediated lysosomal membrane permeabilization and cathepsin B release.
- Temozolomide sensitized cells to proautophagic effects.
- Temozolomide significantly increased survival time in mice compared to cisplatin.
Conclusions:
- Targeting galectin-1 can induce pathways that sensitize melanoma cells to autophagy.
- Temozolomide demonstrates superior therapeutic efficacy over cisplatin in this preclinical melanoma model.
- Modulating galectin-1 and utilizing autophagy-inducing drugs represent a promising strategy for melanoma treatment.
