Increased immunogenicity of colon cancer cells by selective depletion of cytochrome C.
We and others have previously reported in an in vivo rat colon cancer cell model that cell death precedes and is necessary for the development of a specific antitumoral immune response. To sensitize colon cancer cells to death, we depleted cytochrome c by stable transfection with an antisense construct. Cytochrome c depletion sensitizes human and rat colon cancer cells to a nonapoptotic, nonautophagic death induced by various stimuli. This increased sensitization to a necrosis-like cell death may be related to a decrease in cellular ATP levels and an increase in reactive oxygen species production caused by cytochrome c depletion. In vivo, depletion of cytochrome c decreases the tumorigenicity of colon cancer cells in syngeneic rats without influencing their growth in immune-deficient animals. Furthermore, decreased expression of cytochrome c in tumor cells facilitates in vivo "necrotic" cell death and the induction of a specific immune response. These results delineate a novel strategy to sensitize colon cancer cells to chemotherapy and to increase their immunogenicity in immuno-competent hosts.
Schmitt
Elise
E
Institut National de la Santé et de la Recherche Médicale U517, Faculty of Medicine, Dijon, France. cgarrido@u-bourgogne.fr
Parcellier
Arnaud
A
Ghiringhelli
François
F
Casares
Noelia
N
Gurbuxani
Sandeep
S
Droin
Nathalie
N
Hamai
Ahmed
A
Pequignot
Marie
M
Hammann
Arlette
A
Moutet
Monique
M
Fromentin
Annie
A
Kroemer
Guido
G
Solary
Eric
E
Garrido
Carmen
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D016373:DNA, Antisense / Q000235:genetics; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D016373:DNA, Antisense; D005047:Etoposide; D004317:Doxorubicin; D045304:Cytochromes c; D019311:Staurosporine; D002945:Cisplatin