Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of AKT and extracellular signal-regulated kinase (ERK)1/2 |
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Authors: | Yoon Hyunho Min Jeong-Ki Lee Jung Whoi Kim Dae-Ghon Hong Hyo Jeong |
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Affiliation: | aTherapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea;bUniversity of Science and Technology, Daejeon, Republic of Korea;cDepartment of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Chonju, Republic of Korea;dDepartment of Systems Immunology, College of Biomedical Science, and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea |
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Abstract: | Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor and is refractory to conventional chemotherapy. The aim of this study is therefore to elucidate the mechanism of chemoresistance in ICC which is not fully understood. We generated cisplatin resistant ICC cells via long term exposure to cisplatin and found that these cells are also resistant to 5-fluorouracil (5-FU) and gemcitabine. The chemoresistant cells showed enhanced Bcl-2 expression and reduced Bax expression compared to parental ICC cells. In addition, the resistant cells showed enhanced activation of AKT and extracellular signal-regulated kinase (ERK) 1/2. Inhibition of AKT activation by phosphoinocitide 3-kinase (PI3K) inhibitor LY294002 resulted in reduced Bcl-2 expression and enhanced Bax expression and thus induced apoptosis in the resistant cells, whereas inhibition of ERK1/2 activation by mitogen-activated protein kinase (MEK) inhibitor U0126 did not induce apoptosis without affecting the expression of Bcl-2 and Bax but decreased cell growth. Moreover, the inhibition of AKT or ERK1/2 sensitized the resistant cells to cisplatin and therefore resulted in greatly enhanced cisplatin-induced apoptosis and growth inhibition in the cells. The results indicate that AKT and ERK1/2 signaling mediate chemoresistance in the cells and could be important therapeutic targets for overcoming chemoresistance in ICC. |
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Keywords: | Abbreviations: ICC, intrahepatic cholangiocarcinoma ERK1/2, extracellular signal-regulated kinase 1/2 5-FU, 5-fluorouracil MEK, mitogen-activated protein kinase PI3K, phosphoinocitide 3-kinase |
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