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

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-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.

RETRACTED ARTICLE: Silencing UNC5B antisense lncRNA 1 represses growth and metastasis of human Colon cancer cells via raising miR-622

“…To our best knowledge, the regulation of AMPK and PI3K/AKT pathways are complicated. On the basis of several previous researches [35,36], we speculated that miR-622 affected AMPK and PI3K/AKT pathways might through adjusting the up-stream interrelated genes expression of these two pathways. Further researches are still necessary to probe this issue.…”

“…AMPK and PI3K/AKT pathways are proved to be activated in colon cancer [32,33]. It is reported that unusual activations of AMPK and PI3K/AKT pathways contribute to growth, metastasis and drug resistance of colon cancer [34][35][36]. Hereon, silencing UNC5B-AS1 hampered AMPK and PI3K/AKT pathways in HCT116 and Caco-2 cells.…”

Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway

“…The PI3K/AKT pathway is associated with MDR in various cancer cells, such as doxorubicinresistant breast cancer and fluorouracil-resistant colon cancer cells [23,24]. SIRT1 promotes membrane localization and activation of AKT [25].…”

Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer

“…Phospholipase A2 activation results in the release of arachidonic acid, which is the substrate of COX-2, and as a consequence of this activity PGE2 is produced [ 33 ]. This last eicosanoid stimulates proliferation of cells through the Wnt/ β -catenin signalling pathways [ 33 ] and inhibits apoptosis by stabilization of survivin-procaspase 3 complexes [ 34 ]. The effect of IRS-4 on procaspase 3 levels in RKO cells was dependent on PI3K because it was inhibited by wortmannin incubation.…”