Suchergebnisse

Sarcomas are mesenchymal cancers with poor prognosis, representing about 20% of all solid malignancies in children, adolescents, and young adults. Radio- and chemoresistance are common features of sarcomas warranting the search for novel prognostic and predictive markers. GARP/LRRC32 is a TGF-β-activating protein that promotes immune escape and dissemination in various cancers. However, if GARP affects the tumorigenicity and treatment resistance of sarcomas is not known. We show that GARP is expressed by human osteo-, chondro-, and undifferentiated pleomorphic sarcomas and is associated with a significantly worse clinical prognosis. Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis. In contrast, overexpression of GARP promoted their growth in vitro and in vivo and increased their resistance to DNA damage and cell death induced by etoposide, doxorubicin, and irradiation. Our data suggest that GARP could serve as a marker with therapeutic, prognostic, and predictive value in sarcoma. We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy. ; Instituto de Salud Carlos III ; European Union (EU) PI15/00794 PI18/00826 CPII15/00032 PI15/02015 ; Junta de Andalucía C-0013-2018 ; Spanish Government PEJ-2014-A-46314 ; Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER)] SAF-2016-75286-R ; ISCIII/FEDER [Miguel Servet Program] CPII16/00049 ; ISCIII/FEDER [Sara Borrell Program] CD16/00103 ; Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III PT17/0015/0023 ; Fundación Bancaria Cajastur PT17/0015/0023 ; ISCIII/FEDER [Consorcio CIBERONC] CB16/12/00390

Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal cancer (CRC).We selected gallic acid (GA) as a candidate in terms of potency and selectivity and extensively evaluated its biological activity. We report on the role of GA as a ligand of DNA G-quadruplexes (G4s), explaining several of its antitumoral effects, including the transcriptional inhibition of ribosomal and CMYC genes. In addition, GA shared with other established G4 ligands some effects such as cell cycle arrest, nucleolar stress, and induction of DNA damage. We further confirmed the antitumoral and G4-stabilizing properties of GA using a xenograft model of CRC. Finally, we succinctly demonstrate that GA could be explored as a therapeutic agent in a patient cohort with CRC. Our work reveals that GA, a natural bioactive compound present in the diet, affects gene expression by interaction with G4s both in vitro and in vivo and paves the way towards G4s targeting with phenolic compounds. ; Instituto de Salud Carlos III ; European Commission PI21/00497 AC18/00008 ; Next generation EU, Plan de Recuperacion Transformacion y Resiliencia, Agencia Estatal de Investigacion PLEC2021-008094 ; Ministerio de Ciencia e Innovacion from Government of Spain PID2019-104416RB-I00 PID2020-120481RB-I00 ; Ministerio de Universidades from Government of Spain FPU16/05822 FPU17/05413 FPU20/03952 ; University of Almeria FPI-201102