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Akt1 enhances CA916798 expression through mTOR pathway

Yu-Liang Wang1, Bing-Jing Zhu, Zhan-Zhong Qi

  • 1Department of Respiratory Medicine, Southwest Hospital, The Third Military Medical University, Chongqing, China.

Plos One
|May 14, 2013
PubMed

Insights

Overexpression of CA916798 contributes to multi-drug resistance in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway. Inhibiting this pathway reduces CA916798 levels and tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Multi-drug resistance (MDR) is a major challenge in cancer chemotherapy.
  • Our prior research linked CA916798 overexpression to MDR, but the mechanism was unclear.

Purpose of the Study:

  • To elucidate the mechanism by which CA916798 contributes to drug resistance in lung adenocarcinoma.
  • To investigate the role of the PI3K/AKT/mTOR pathway in regulating CA916798 expression and its impact on chemoresistance.

Main Methods:

  • Analysis of phosphorylated AKT, mTOR, and CA916798 levels in drug-resistant human adenocarcinoma samples.
  • Immunofluorescence and Co-immunoprecipitation (Co-IP) assays to assess CA916798 and AKT1 interaction.
  • In vitro studies using A549 and A549/CDDP cell lines.
  • In vivo studies using xenografted tumors in nude mice.
  • Pharmacological inhibition of PI3K (LY294002) and mTORC1 (rapamycin).

Main Results:

  • Elevated levels of phosphorylated AKT, phosphorylated mTOR, and CA916798 were observed in drug-resistant samples, correlating with resistance.
  • CA916798 expression positively correlated with AKT1 activation, suggesting a link to lung adenocarcinoma drug resistance.
  • AKT1 stimulates CA916798 expression via the mTOR pathway, with CA916798 downstream of PI3K/AKT/mTOR.
  • PI3K inhibition (LY294002) reduced CA916798 expression and tumor size in vivo.
  • Combined PI3K and mTORC1 inhibition showed a stronger effect on reducing CA916798 and tumor size.

Conclusions:

  • CA916798 plays a crucial role in mediating multi-drug resistance in lung adenocarcinoma.
  • The PI3K/AKT/mTOR pathway regulates CA916798 expression, contributing to chemoresistance.
  • Targeting the PI3K/AKT/mTOR pathway, potentially with combined inhibitors, offers a promising strategy for overcoming drug resistance in lung adenocarcinoma.

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