Research Papers:

Over-activation of AKT signaling leading to 5-Fluorouracil resistance in SNU-C5/5-FU cells

Eun-Ji Kim, Gyeoung-Jin Kang, Jung-Il Kang, Hye-Jin Boo, Jin Won Hyun, Young Sang Koh, Weon-Young Chang, Young Ree Kim, Jung-Mi Kwon, Young Hee Maeng, Eun-Sook Yoo, Chang Hoon Lee and Hee-Kyoung Kang _

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Oncotarget. 2018; 9:19911-19928. https://doi.org/10.18632/oncotarget.24952

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Eun-Ji Kim1, Gyeoung-Jin Kang1,2, Jung-Il Kang2, Hye-Jin Boo2,3, Jin Won Hyun2, Young Sang Koh2, Weon-Young Chang2, Young Ree Kim2, Jung-Mi Kwon2,4, Young Hee Maeng2, Eun-Sook Yoo2, Chang Hoon Lee1 and Hee-Kyoung Kang2

1College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea

2Department of Medicine, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea

3Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

4Department of Internal Medicine, Jeju National University Hospital, Jeju 63241, Republic of Korea

Correspondence to:

Hee-Kyoung Kang, email: [email protected]

Keywords: SNU-C5/5-FU; 5-Fluorouracil resistance; over-activation of AKT; E-cadherin; COX-2

Received: January 10, 2018     Accepted: March 13, 2018     Published: April 13, 2018


Here, we investigated whether over-activation of AKT pathway is important in the resistance to 5-fluorouracil (5-FU) in SNU-C5/5-FU cells, 5-FU-resistant human colon cancer cells. When compared to wild type SNU-C5 cells (WT), SNU-C5/5-FU cells showed over-activation of PI3K/AKT pathway, like increased phosphorylation of AKT, mTOR, and GSK-3β, nuclear localization of β-catenin, and decreased E-cadherin. Moreover, E-cadherin level was down-regulated in recurrent colon cancer tissues compared to primary colon cancer tissues. Gene silencing of AKT1 or treatment of LY294002 (PI3 kinase inhibitor) increased E-cadherin, whereas decreased phospho-GSK-3β. LY294002 also reduced protein level of β-catenin with no influence on mRNA level. PTEN level was higher in SNU-C5/WT than SNU-C5/5-FU cells, whereas the loss of PETN in SNU-C5/WT cells induced characteristics of SNU-C5/5-FU cells. In SNU-C5/5-FU cells, NF-κB signaling was activated, along with the overexpression of COX-2 and stabilization of survivin. However, increased COX-2 contributed to the stabilization of survivin, which directly interacts with cytoplasmic procaspase-3, while the inhibition of AKT reduced this cascade. We finally confirmed that combination treatment with 5-FU and LY294002 or Vioxx could induce apoptosis in SNU-C5/5-FU cells. These data suggest that inhibition of AKT activation may overcome 5-FU-resistance in SNU-C5/5-FU cells. These findings provide evidence that over-activation of AKT is crucial for the acquisition of resistance to anticancer drugs and AKT pathway could be a therapeutic target for cancer treatment.

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