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Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Kazuhiro Yamamoto, Atsushi Uda, Akira Mukai

    Journal of Experimental & Clinical Cancer Research : CR
    |January 16, 2014
    PubMed
    Abstract

    Insights

    Signal transducer and activator of transcription 3 (STAT3) activity may predict skin side effects from the mTOR inhibitor everolimus. Inhibiting STAT3 enhanced everolimus

    Area of Science:

    • Oncology
    • Dermatology
    • Molecular Biology

    Background:

    • Mammalian target of rapamycin (mTOR) inhibitors can cause skin issues.
    • Everolimus, an mTOR inhibitor, is linked to dermatological adverse events.
    • The role of signal transducer and activator of transcription 3 (STAT3) in these events is unclear.

    Purpose of the Study:

    • To investigate the relationship between STAT3 protein and everolimus-induced dermatological adverse events.
    • To explore STAT3's role in everolimus's effects on keratinocytes.

    Main Methods:

    • Utilized WST-8 and western blot analyses to assess everolimus effects on HaCaT cells.
    • Investigated STAT3 activity, cell growth inhibition, and apoptosis.
    • Examined the impact of STAT3 inhibitors (stattic, STA-21) and p38 MAPK inhibitor.

    Main Results:

    • STAT3 inhibition enhanced everolimus's cell growth inhibitory effects in HaCaT cells.
    • Everolimus decreased STAT3 phosphorylation at tyrosine 705 in HaCaT cells.
    • STAT3 activation and p38 MAPK inhibition partially resisted everolimus's cytostatic activity.

    Conclusions:

    • STAT3 activity may serve as a predictive biomarker for everolimus-induced dermatological toxicity.
    • Understanding STAT3 signaling is crucial for managing everolimus side effects.

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