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STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1

María Elisa Picco1, María Victoria Castro2, María Josefina Quezada2

  • 11Instituto de Medicina y Biología Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.

Cell & Bioscience
|January 10, 2019
PubMed
Abstract

Insights

Signal transducer and activator of transcription 3 (STAT3) directly regulates 3-phosphoinositide-dependent kinase 1 (PDK1) transcription. This STAT3-PDK1 link affects AGC kinase activity and cell survival in melanoma, suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • The PI3K/Akt and STAT3 pathways are functionally linked in various cancers.
  • The precise mechanism connecting STAT3 activity to Akt activity remains poorly understood.
  • Melanoma cells were used as a model to investigate this relationship.

Purpose of the Study:

  • To elucidate the mechanism by which STAT3 influences Akt and other AGC kinase activity.
  • To identify the specific molecular links between STAT3 and AGC kinase signaling in cancer.

Main Methods:

  • Investigated STAT3 binding to the PDK1 promoter.
  • Utilized STAT3-small hairpin RNA (shRNA) to assess the impact of STAT3 knockdown on PDK1 expression and AGC kinase phosphorylation.
  • Employed expression of HA-PDK1 to evaluate rescue effects on cell death and Bcl2 protein levels.

Main Results:

  • Active STAT3 was found to bind the PDK1 promoter, enhancing its transcription.
  • STAT3 knockdown reduced PDK1 mRNA and protein levels, consequently decreasing phosphorylation of Akt, PKC, and SGK.
  • Overexpression of HA-PDK1 restored Akt phosphorylation, inhibited dacarbazine-induced cell death, and rescued Bcl2 family protein levels.

Conclusions:

  • PDK1 is identified as a direct transcriptional target of STAT3, establishing a link between the STAT3 pathway and AGC kinase activity in melanoma.
  • These findings support therapeutic strategies targeting both STAT3 and PDK1 in melanoma and potentially other cancers.
Keywords:
AktMelanomaPDK1PKCSGKSTAT3

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