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, Hee Kyoung Kang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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-FUresistance 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.

Original languageEnglish (US)
Pages (from-to)19911-19928
Number of pages18
JournalOncotarget
Volume9
Issue number28
DOIs
StatePublished - Apr 13 2018

Bibliographical note

Funding Information:
This research was supported by a grant from the Basic Research Laboratory Program (NRF-2017R1A4A1014512) by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP), by Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2016R1D1A1B01010337) and by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (No. 1120340)

Publisher Copyright:
© Kim et al.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • 5-Fluorouracil resistance
  • COX-2
  • E-cadherin
  • Over-activation of AKT
  • SNU-C5/5-FU

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