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The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1/PKBα isoform signaling

K Sully1, O Akinduro, M P Philpott

  • 1Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Oncogene
|August 15, 2012
PubMed

Insights

The immunosuppressant drug rapamycin may prevent skin cancer (squamous cell carcinoma) by boosting epidermal Akt1 signaling, potentially counteracting damaging effects of UV radiation and tumor development.

Area of Science:

  • Dermatology
  • Oncology
  • Immunology

Background:

  • Epidermal squamous cell carcinoma (SCC) is an aggressive skin cancer with increased incidence in immunosuppressed organ transplant recipients.
  • The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, reduces SCC occurrence post-transplantation, but its mechanism remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which rapamycin reduces SCC in immunosuppressed patients.
  • To explore the role of Akt1 and Akt2 signaling pathways in rapamycin's chemopreventive effects against SCC.

Main Methods:

  • Analyzing epidermal Akt1 and Akt2 expression and phosphorylation in response to rapamycin treatment.
  • Investigating the effect of UV radiation on Akt1 and Akt2 signaling in skin.
  • Examining rapamycin's impact on Akt1 phosphorylation in UV-irradiated skin cultures.

Main Results:

  • Rapamycin selectively upregulates epidermal Akt1, not Akt2, via inhibition of mTOR complex 1 and insulin receptor substrate-1.
  • UV radiation downregulates epidermal Akt1 and upregulates Akt2, mirroring changes seen in SCC.
  • Rapamycin enhances Akt1 phosphorylation recovery in UV-irradiated skin, suggesting a protective mechanism.

Conclusions:

  • Rapamycin's upregulation of epidermal Akt1 signaling may counteract UV-induced damage and tumor-associated alterations.
  • This Akt1-mediated pathway offers a potential mechanism for rapamycin's chemopreventive effects against SCC in transplant recipients.

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