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CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

Authors Yang K, Gao K, Hu G, Wen Y, Lin C, Li X

Received 21 March 2016

Accepted for publication 7 August 2016

Published 30 November 2016 Volume 2016:9 Pages 7285—7295

DOI https://doi.org/10.2147/OTT.S108929

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Jia Fan

Peer reviewer comments 3

Editor who approved publication: Professor Min Li


Kai Yang, Kai Gao, Gui Hu, Yanguang Wen, Changwei Lin, Xiaorong Li

Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People’s Republic of China

Abstract: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC.

Keywords: connective tissue growth factor, 5-fluorouracil, mitogen-activated protein kinase/extracellular regulated protein kinases, phosphatidyl inositol 3-kinase/serine/threonine kinase Akt, colorectal cancer

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