The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells
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Gabriele Romano1, Ludovica Santi1, Maria Rosaria Bianco2, Maria Rita Giuffrè1, Mariateresa Pettinato1, Cristina Bugarin3, Cristina Garanzini1, Leonilde Savarese4, Silvia Leoni1, Maria Grazia Cerrito1, Biagio Eugenio Leone1, Giuseppe Gaipa3, Emanuela Grassilli1, Michele Papa4, Marialuisa Lavitrano1, Roberto Giovannoni1
1Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900, Monza, Italy
2Department 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
3M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900 Monza, Italy
4Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, 80138, Naples, Italy
Roberto Giovannoni, e-mail: [email protected]
Keywords: TGF-β, chemoresistance, 5-fluorouracil, colorectal cancer, SMAD3
Received: October 12, 2015 Accepted: February 20, 2016 Published: March 03, 2016
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.
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