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Identification of novel regulators of STAT3 activity

Elina Parri1, Heikki Kuusanmäki1,2, Arjan J van Adrichem1

  • 1Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

Plos One
|April 2, 2020
PubMed

Insights

Constitutive STAT3 activation protects cancer cells from cytotoxic drugs. A kinase and phosphatase siRNA screen identified novel STAT3 regulators, including CDC7 and CSNK2, offering potential therapeutic targets for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor regulating oncogenes and cell survival.
  • Persistent STAT3 activation, primarily via tyrosine phosphorylation at Y705, is implicated in numerous cancers.
  • Constitutive STAT3 activation confers resistance to various cytotoxic drugs, highlighting its role in cancer progression and treatment failure.

Purpose of the Study:

  • To identify novel regulators of STAT3 signaling.
  • To explore potential therapeutic targets for inhibiting STAT3 activity in cancer.

Main Methods:

  • Performed a kinase and phosphatase siRNA screen in cells with hyperactive or IL6-induced STAT3.
  • Utilized small molecule inhibitors to validate identified STAT3 regulators.
  • Assessed STAT3-mediated transcriptional activity.

Main Results:

  • Identified CDC7, CSNK2, DDR2, CDK8, PI4KII, CSK, and PTPRH as potential STAT3 regulators.
  • Confirmed that small molecule inhibitors targeting these kinases dose-dependently inhibit STAT3-mediated transcription.
  • Demonstrated that inhibiting these kinases can dampen STAT3 activity.

Conclusions:

  • Novel kinases and phosphatases regulating STAT3 activity have been identified.
  • Targeting these newly identified regulators, such as CDC7 and CSNK2, may offer effective strategies to inhibit STAT3 in cancer therapy.
  • This research provides a foundation for developing new therapeutic approaches to overcome STAT3-driven drug resistance in cancer.

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