TY - JOUR
T1 - The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells
AU - Romano, Gabriele
AU - Santi, Ludovica
AU - Bianco, Maria Rosaria
AU - Giuffrè, Maria Rita
AU - Pettinato, Mariateresa
AU - Bugarin, Cristina
AU - Garanzini, Cristina
AU - Savarese, Leonilde
AU - Leoni, Silvia
AU - Cerrito, Maria Grazia
AU - Leone, Biagio Eugenio
AU - Gaipa, Giuseppe
AU - Grassilli, Emanuela
AU - Papa, Michele
AU - Lavitrano, Marialuisa
AU - Giovannoni, Roberto
N1 - Funding Information:
This work was supported by grants from MIUR [PON01_02782 to M.L.], Ministry of Health [RF-2010-2305526 to M.L.] and University of Milano-Bicocca [F.A.R. to M.L. and R.G.].
PY - 2016/4/19
Y1 - 2016/4/19
N2 - 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 5FUtreated 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.
AB - 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 5FUtreated 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.
KW - 5-fluorouracil
KW - Chemoresistance
KW - Colorectal cancer
KW - SMAD3
KW - TGF-β
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U2 - 10.18632/oncotarget.7895
DO - 10.18632/oncotarget.7895
M3 - Article
C2 - 26956045
AN - SCOPUS:84965081790
SN - 1949-2553
VL - 7
SP - 22077
EP - 22091
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -