The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.
The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells.
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DOI：
10.18632/oncotarget.7895
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Giovannoni R
中科院分区：
文献类型：
--
作者：
Romano G;Santi L;Bianco MR;Giuffrè MR;Pettinato M;Bugarin C;Garanzini C;Savarese L;Leoni S;Cerrito MG;Leone BE;Gaipa G;Grassilli E;Papa M;Lavitrano M;Giovannoni R
转化生长因子-β通路广泛参与肿瘤的转移、血管生成和内皮细胞转移过程。然而，关于转化生长因子-β在癌症耐药中的作用，人们知之甚少。在这项工作中，我们展示了在体内和体外结直肠癌模型中化疗导致转化生长因子-β通路的特异性激活。5-氟尿嘧啶(5FU)能刺激Smad3的激活和ACVRL1、FN1、TGFB1等特异性基因的转录。另一方面，特异性抑制βRI可抑制5FU诱导的基因转录，并通过降低BCL2L1和ID1基因的表达，恢复化疗耐药细胞对药物毒性作用的敏感性。条件培养液(CM)实验进一步证实了转化生长因子-β分子在化疗耐药细胞对5FU的反应中的作用：5FU处理的化疗耐药细胞的CM能够保护化疗敏感细胞免受5FU的毒性作用。综上所述，这些发现表明转化生长因子-β通路在结肠癌耐药机制中的关键作用，为结肠癌患者的诊断和治疗提供了新的可能途径。
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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影响因子：
5.7
作者：
Basu, Dipanjan;Lettan, Robert;Rebbaa, Abdelhadi
通讯作者：
Rebbaa, Abdelhadi
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
DOI：
10.1165/ajrcmb/8.4.417
发表时间：
1993-04-01
影响因子：
6.4
作者：
KELLEY, J;SHULL, S;ABSHER, M
通讯作者：
ABSHER, M
DOI：
10.1083/jcb.201102147
发表时间：
2012-02-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lu P;Weaver VM;Werb Z
通讯作者：
Werb Z
影响因子：
14.9
作者：
Edgar, R;Domrachev, M;Lash, AE
通讯作者：
Lash, AE