Statins stimulate in vitro membrane FasL expression and lymphocyte apoptosis through RhoA/ROCK pathway in murine melanoma cells.
The capacity of FasL molecules expressed on melanoma cells to induce lymphocyte apoptosis contributes to either antitumor immune response or escape depending on their expression level. Little is known, however, about the mechanisms regulating FasL protein expression. Using the murine B16F10 melanoma model weakly positive for FasL, we demonstrated that in vitro treatment with statins, inhibitors of 3-hydroxy-3-methylgutaryl CoA reductase, enhances membrane FasL expression. C3 exotoxin and the geranylgeranyl transferase I inhibitor GGTI-298, but not the farnesyl transferase inhibitor FTI-277, mimic this effect. The capacity of GGTI-298 and C3 exotoxin to inhibit RhoA activity prompted us to investigate the implication of RhoA in FasL expression. Inhibition of RhoA expression by small interfering RNA (siRNA) increased membrane FasL expression, whereas overexpression of constitutively active RhoA following transfection of RhoAV14 plasmid decreased it. Moreover, the inhibition of a RhoA downstream effector p160ROCK also induced this FasL overexpression. We conclude that the RhoA/ROCK pathway negatively regulates membrane FasL expression in these melanoma cells. Furthermore, we have shown that B16F10 cells, through the RhoA/ROCK pathway, promote in vitro apoptosis of Fas-sensitive A20 lymphoma cells. Our results suggest that RhoA/ROCK inhibition could be an interesting target to control FasL expression and lymphocyte apoptosis induced by melanoma cells.
Sarrabayrouse
Guillaume
G
INSERM, U563, Toulouse, F-31300 France.
Synaeve
Cindy
C
Leveque
Kevin
K
Favre
Gilles
G
Tilkin-Mariamé
Anne-Françoise
AF
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D036002:ADP Ribose Transferases / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D001549:Benzamides / Q000494:pharmacology; D001905:Botulinum Toxins / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000166:cytology; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008214:Lymphocytes / Q000166:cytology*; D008223:Lymphoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019014:fas Receptor / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D000590:Amino Acid Chloromethyl Ketones; D001549:Benzamides; C096856:FTI 277; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C102521:GGTI 298; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C015367:mevalonolactone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000069059:Atorvastatin; D008715:Methionine; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid