Inhibition of mycobacterial infection by the tumor suppressor PTEN

Guochang Huang1, Gil Redelman-Sidi, Neal Rosen

  • 1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Insights

The tumor suppressor PTEN regulates cellular infection susceptibility. PTEN deficiency increases susceptibility to mycobacterial pathogens, while inhibiting related signaling pathways like PI3K-Akt-mTOR can reduce infection levels.

Area of Science:

  • Cellular Biology
  • Cancer Biology
  • Infectious Disease

Background:

  • The tumor suppressor PTEN is crucial in cancer, primarily by inhibiting the PI3K-Akt pathway.
  • PTEN's role in cellular functions beyond tumor suppression, particularly in infection resistance, is not well understood.
  • The interplay between cancer-related signaling pathways and susceptibility to pathogens remains an area needing definition.

Purpose of the Study:

  • To investigate the role of PTEN signaling in regulating cellular susceptibility to mycobacterial infections.
  • To determine if pharmacological modulation of PTEN signaling affects mycobacterial infection levels.
  • To explore the connection between the PTEN-PI3K-Akt-mTOR pathway and intracellular pathogen load.

Main Methods:

  • Assessed PTEN's impact on infection susceptibility in various cell types (noncancerous and cancerous).
  • Utilized pharmacological inhibitors targeting PI3K, Akt, and mTOR pathways.
  • Quantified intracellular mycobacterial loads (Mycoplasma and Mycobacterium bovis BCG).

Main Results:

  • PTEN deficiency significantly increased cellular susceptibility to Mycoplasma and Mycobacterium bovis BCG infections.
  • The lipid phosphatase activity of PTEN was essential for its infection-attenuating function.
  • Mycobacterial infection induced Akt phosphorylation, and inhibiting PI3K or Akt reduced intracellular infection.
  • Inhibition of mTOR also decreased intracellular Mycobacterium bovis BCG levels in cancer cells.

Conclusions:

  • PTEN signaling plays a critical role in modulating cellular defense against mycobacterial pathogens.
  • The PI3K-Akt-mTOR pathway is a key mediator of PTEN's influence on infection susceptibility.
  • Genetic alterations in PTEN within cancer cells may impact their interaction with mycobacterial infections.

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