Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma.
When overexpressed, the stress protein heat shock protein 70 (HSP70) increases the oncogenic potential of cancer cells in rodent models. HSP70 also prevents apoptosis, thereby increasing the survival of cells exposed to a wide range of otherwise lethal stimuli. These protective functions of HSP70 involve its interaction with and neutralization of the adaptor molecule apoptotic protease activation factor-1, implicated in caspase activation, and the flavoprotein apoptosis-inducing factor (AIF), involved in caspase-independent cell death. We have shown previously that a peptide containing the AIF sequence involved in its interaction with HSP70 (ADD70, amino acids 150-228) binds to and neutralizes HSP70 in the cytosol, thereby sensitizing cancer cells to apoptosis induced by a variety of death stimuli. Here, we show that expression of ADD70 in tumor cells decreases their tumorigenicity in syngeneic animals without affecting their growth in immunodeficient animals. ADD70 antitumorigenic effects are associated with an increase in tumor-infiltrating cytotoxic CD8+ T cells. In addition, ADD70 sensitizes rat colon cancer cells (PROb) and mouse melanoma cells (B16F10) to the chemotherapeutic agent cisplatin. ADD70 also shows an additive effect with HSP90 inhibition by 17-allylamino-17-demethoxygeldanamycin in vitro. Altogether, these data indicate the potential interest of targeting the HSP70 interaction with AIF for cancer therapy.
Schmitt
Elise
E
Institut National de la Sante et de la Recherche Medicale, Faculty of Medicine, Dijon, France.
Maingret
Loic
L
Puig
Pierre-Emmanuel
PE
Rerole
Anne-Laure
AL
Ghiringhelli
François
F
Hammann
Arlette
A
Solary
Eric
E
Kroemer
Guido
G
Garrido
Carmen
C
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis / Q000235:genetics*; D016227:Benzoquinones; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011923:Rats, Nude; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection
D051033:Apoptosis Inducing Factor; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010446:Peptide Fragments; D017828:Rifabutin; C112765:tanespimycin; D002945:Cisplatin