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Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration

Myoung W Lee1, Dae S Kim, Joo H Lee

  • 1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Cancer Science
|July 5, 2011
PubMed

Insights

AKT1 and AKT2 play distinct roles in non-small cell lung cancer (NSCLC) cell survival. AKT1 inhibition impacts growth and migration, while AKT2 affects apoptosis, with both enhancing cisplatin sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Constitutive activation of AKT (protein kinase B) is common in non-small cell lung cancer (NSCLC).
  • AKT is a potential target for enhancing cancer therapeutic cytotoxicity.
  • The specific roles of AKT isoforms (AKT1, AKT2) in NSCLC remain largely undefined.

Purpose of the Study:

  • To investigate the distinct functions of AKT1 and AKT2 in NSCLC cells.
  • To determine how targeting AKT isoforms influences chemosensitivity to cisplatin.
  • To elucidate the downstream signaling pathways affected by AKT1 and AKT2 inhibition.

Main Methods:

  • Utilized RNA interference (RNAi) with small interfering RNA (siRNA) to selectively knockdown AKT1 and AKT2 in NSCLC cell lines (A549, H460).
  • Assessed apoptosis, mitochondrial membrane potential, caspase activation, and cell cycle progression.
  • Evaluated MEK/ERK1/2 activity, nuclear factor-kappaB (NF-κB) activation, and expression of apoptosis-related proteins (MCL-1, p27).
  • Measured colony formation and cell migration capabilities.

Main Results:

  • siRNA targeting of AKT1 or AKT2 effectively reduced their respective protein levels.
  • Knockdown of AKT1 decreased MEK/ERK1/2 activity and increased NF-κB activation.
  • Knockdown of AKT2 induced MCL-1 cleavage, mitochondrial dysfunction, and caspase cascade activation.
  • Both AKT1 and AKT2 siRNA treatments enhanced cisplatin-induced apoptosis and chemosensitivity in H460 cells.
  • AKT1 siRNA significantly reduced colony formation and migration, while AKT2 siRNA had no significant effect on these parameters.
  • Neither AKT1 nor AKT2 siRNA significantly affected p27 expression or induced statistically significant G2/M phase arrest.

Conclusions:

  • AKT1 and AKT2 contribute to NSCLC cell survival through different mechanisms.
  • AKT1 predominantly regulates cell growth and migration.
  • AKT2 plays a key role in regulating apoptosis via the mitochondrial pathway.
  • Targeting specific AKT isoforms may offer refined strategies to sensitize NSCLC cells to chemotherapy.

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