Targeting TCTP as a new therapeutic strategy in castration-resistant prostate cancer.
Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells.
Inserm, UMR1068, Molecular Oncology Department, Marseille Cancerology Research Center, CRCM, Marseille, France.
Virginie
V
Baylot
Maria
M
Katsogiannou
Claudia
C
Andrieu
David
D
Taieb
Julie
J
Acunzo
Sophie
S
Giusiano
Ladan
L
Fazli
Martin
M
Gleave
Carmen
C
Garrido
Palma
P
Rocchi
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002369:Castration; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000601:surgery*; D043823:Taxoids / Q000627:therapeutic use; D000090324:Tumor Protein, Translationally-Controlled 1; D020798:Two-Hybrid System Techniques
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D055551:HSP27 Heat-Shock Proteins; C000715647:TPT1 protein, human; D043823:Taxoids; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D000077143:Docetaxel