Anticancer activity of targeted proapoptotic peptides and chemotherapy is highly improved by targeted cell surface calreticulin-inducer peptides.
We have recently identified (a) ectocalreticulin as the main source of immunogenicity of cancer cell death induced by chemotherapy or radiotherapy, (b) ectoERP57 as critical protein for inducing cell surface exposure of calreticulin, and (c) that ectoERP57 and ectocalreticulin are cotranslocated together to the tumor cell surface by the mediator of the inhibition of PP1/GADD34 complex. Here, I report that the immunogenicity of cancer cell death induced by anticancer targeted proapoptotic peptides is also dictated by ectocalreticulin. To improve the anticancer activity of these proapoptotic peptides, I have designed several targeted chimeric inhibitor peptides of the PP1/GADD34 complex, which are comprised of an inhibitor peptide of the PP1/GADD34 complex fused to a protein transduction domain-5, to prostate homing peptide, or to the tumor antigen BiP/GRP78-binding peptide motifs. These inhibitor peptides (a) induce ectocalreticulin and ectoERP57 in a variety of tumor cell lines by the mediator of the inhibition of the interaction between PP1 and GADD34, (b) increase the phagocytosis of anticancer targeted proapoptotic peptide-treated tumor cells by dendritic cells, and (c) improve highly the anticancer activity of proapoptotic peptides and chemotherapy by suppressing or reducing the tumor growth in several isogenic mouse models of colon, mammary, and fibrosarcoma tumors and by increasing the lifespan of transgenic adenocarcinoma mouse prostate mice. These results suggest (a) that the inhibition of PP1/GADD34 complex is a key element to improve the anticancer activity of targeted proapoptotic peptides and chemotherapy and (b) that these targeted peptides combination approach could serve as a new powerful autonomous anticancer therapy.
Obeid
Michel
M
GenCal, 43 Rue Violet, F-75015 Paris, France. michel.obeid@yahoo.fr
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D037282:Calreticulin / Q000096:biosynthesis*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D037282:Calreticulin; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; D010455:Peptides