The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

// Gabriele Romano 1 , Ludovica Santi 1 , Maria Rosaria Bianco 2 , Maria Rita Giuffre 1 , Mariateresa Pettinato 1 , Cristina Bugarin 3 , Cristina Garanzini 1 , Leonilde Savarese 4 , Silvia Leoni 1 , Maria Grazia Cerrito 1 , Biagio Eugenio Leone 1 , Giuseppe Gaipa 3 , Emanuela Grassilli 1 , Michele Papa 4 , Marialuisa Lavitrano 1 , Roberto Giovannoni 1 1 Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy 2 Department of Surgery and Translational Medicine, University of Milano-Bicocca, c/o Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy 3 M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900 Monza, Italy 4 Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy Correspondence to: Roberto Giovannoni, e-mail: roberto.giovannoni@unimib.it Keywords: TGF-β, chemoresistance, 5-fluorouracil, colorectal cancer, SMAD3 Received: October 12, 2015      Accepted: February 20, 2016      Published: March 03, 2016 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.