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Published on: July 20, 2019
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.
Abstract:
The tumor suppressor PTEN is a lipid phosphatase that is frequently mutated in various human cancers. PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. In addition to it role in tumor suppression, the PTEN-PI3K pathway controls many cellular functions, some of which may be important for cellular resistance to infection. Currently, the intersection between tumorigenic signaling pathways and cellular susceptibility to infection is not well defined. In this study we report that PTEN signaling regulates infection of both noncancerous and cancerous cells by multiple intracellular mycobacterial pathogens and that pharmacological modulation of PTEN signaling can affect mycobacterial infection. We found that PTEN deficiency renders multiple types of cells hyper-susceptible to infection by Mycoplasma and Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The lipid phosphatase activity of PTEN is required for attenuating infection. Furthermore, we found mycobacterial infection activates host cell Akt phosphorylation, and pharmacological inhibition of Akt or PI3K activity reduced levels of intracellular infection. Intriguingly, inhibition of mTOR, one of the downstream components of the Akt signaling and a promising cancer therapeutic target, also lowered intracellular Bacillus Calmette-Guérin levels in mammary epithelial cancer MCF-7 cells. These findings demonstrate a critical role of PTEN-regulated pathways in pathogen infection. The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells.
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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