AKT1 E17K inhibits cancer cell migration by abrogating β-catenin signaling Journal Article

Authors: Gao, S. P.; Kiliti, A. J.; Zhang, K.; Vasani, N.; Mao, N.; Jordan, E.; Wise, H. C.; Shrestha Bhattarai, T.; Hu, W.; Dorso, M.; Rodrigues, J. A.; Kim, K.; Hanrahan, A. J.; Razavi, P.; Carver, B.; Chandarlapaty, S.; Reis-Filho, J. S.; Taylor, B. S.; Solit, D. B.
Article Title: AKT1 E17K inhibits cancer cell migration by abrogating β-catenin signaling
Abstract: Mutational activation of the PI3K/AKT pathway is among the most common pro-oncogenic events in human cancers. The clinical utility of PI3K and AKT inhibitors has, however, been modest to date. Here, we used CRISPR-mediated gene editing to study the biological consequences of AKT1 E17K mutation by developing an AKT1 E17K-mutant isogenic system in a TP53-null background. AKT1 E17K expression under the control of its endogenous promoter enhanced cell growth and colony formation, but had a paradoxical inhibitory effect on cell migration and invasion. The mechanistic basis by which activated AKT1 inhibited cell migration and invasion was increased E-cadherin expression mediated by suppression of ZEB1 transcription via altered b-catenin subcellular localization. This phenotypic effect was AKT1-specific, as AKT2 activation had the opposite effect, a reduction in E-cadherin expression. Consistent with the opposing effects of AKT1 and AKT2 activation on E-cadherin expression, a promigratory effect of AKT1 activation was not observed in breast cancer cells with PTEN loss or expression of an activating PIK3CA mutation, alterations which induce the activation of both AKT isoforms. The results suggest that the use of AKT inhibitors in patients with breast cancer could paradoxically accelerate metastatic progression in some genetic contexts and may explain the frequent coselection for CDH1 mutations in AKT1-mutated breast tumors. © 2020 American Association for Cancer Research.
Journal Title: Molecular Cancer Research
Volume: 19
Issue: 4
ISSN: 1541-7786
Publisher: American Association for Cancer Research  
Date Published: 2021-04-01
Start Page: 573
End Page: 584
Language: English
DOI: 10.1158/1541-7786.Mcr-20-0623
PUBMED: 33303690
PROVIDER: scopus
PMCID: PMC8026572
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. David Solit
    653 Solit
  2. Brett Stewart Carver
    133 Carver
  3. Wenhuo Hu
    51 Hu
  4. Sizhi Gao
    38 Gao
  5. Barry Stephen Taylor
    232 Taylor
  6. Pedram Razavi
    112 Razavi
  7. Emmet John Jordan
    46 Jordan
  8. Kwanghee   Kim
    29 Kim
  9. Hannah Christina Johnsen
    10 Johnsen
  10. Ninghui   Mao
    15 Mao
  11. Madeline Anne Dorso
    4 Dorso
  12. Naresh B Vasani
    3 Vasani
  13. Kai Zhang
    3 Zhang