Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model.
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.
Mathieu
Véronique
V
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Brussels, Belgium.
Le Mercier
Marie
M
De Neve
Nancy
N
Sauvage
Sébastien
S
Gras
Thierry
T
Roland
Isabelle
I
Lefranc
Florence
F
Kiss
Robert
R
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D037483:Galectin 1 / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D037483:Galectin 1; D050884:HSP72 Heat-Shock Proteins; D034741:RNA, Small Interfering; D003606:Dacarbazine; D002401:Cathepsin B; D002945:Cisplatin; D000077204:Temozolomide