Genetic deletion and pharmacological inhibition of Akt1 isoform attenuates bladder cancer cell proliferation, motility and invasion

Eur J Pharmacol. 2015 Oct 5:764:208-214. doi: 10.1016/j.ejphar.2015.06.059. Epub 2015 Jul 3.

Abstract

Isoform specific expression, intracellular localization and function of Akt in bladder cancer are not known. In the current study, we identified Akt1, followed by Akt2 and Akt3 as the predominant Akt isoform in human T24 and UM-UC-3 metastatic bladder cancer cells. Whereas Akt1 is localized at the membrane, cytoplasm and nucleus, Akt2 is solely cytoplasmic and Akt3 is mostly localized in the nucleus in T24 cells. ShRNA-mediated Akt1 knockdown resulted in impaired T24 cell survival, proliferation, colony formation, migration and microinvasion. Whereas pharmacological inhibition of Akt1 resulted in impaired T24 and UM-UC-3 cell motility, viability and proliferation, effect of pharmacological inhibition by Akt2 inhibitor was limited to proliferation in T24, but not UM-UC-3 cells. Our data provide important clues on the therapeutic benefits of targeting Akt1 for bladder cancer therapy.

Keywords: Akt1; Akt2; Akt3; Bladder cancer; Invasion; Proliferation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cytoplasm / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • RNA, Small Interfering / genetics
  • Urinary Bladder Neoplasms / metabolism*

Substances

  • 4-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-amine
  • Pyrimidines
  • Pyrroles
  • RNA, Small Interfering
  • AKT1 protein, human
  • AKT2 protein, human
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt