title: The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.
abstract: TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients.
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Santi
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Bianco
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Giuffrè
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Pettinato
authors.affiliation: M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900, Monza, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bugarin
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Garanzini
authors.affiliation: Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy.
authors.forename: Leonilde
authors.initials: L
authors.lastname: Savarese
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoni
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cerrito
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Biagio Eugenio
authors.initials: BE
authors.lastname: Leone
authors.affiliation: M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900, Monza, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gaipa
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Grassilli
authors.affiliation: Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Papa
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D005472:Fluorouracil
keywords: 5-fluorouracil; SMAD3; TGF-β; chemoresistance; colorectal cancer