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STAT3 and mutp53 Engage a Positive Feedback Loop Involving HSP90 and the Mevalonate Pathway

Maria Anele Romeo1,2, Maria Saveria Gilardini Montani1,2, Rossella Benedetti1,2

  • 1Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.

Frontiers in Oncology
|August 6, 2020
PubMed

Insights

Mutant TP53 (mutp53) and STAT3 form a cancer-promoting alliance. Inhibiting STAT3 reduces mutp53 levels by targeting HSP90 and the mevalonate pathway, revealing a novel therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The tumor suppressor TP53 and oncogene STAT3 normally inhibit each other.
  • Mutant p53 (mutp53) may sustain STAT3 phosphorylation, but STAT3's effect on mutp53 is unknown.

Purpose of the Study:

  • To investigate the interplay between mutant p53 and STAT3 in cancer.
  • To elucidate the mechanisms by which mutp53 and STAT3 influence each other's expression and activity.

Main Methods:

  • Pharmacologic and genetic inhibition of STAT3 in glioblastoma and pancreatic cancer cell lines.
  • Analysis of HSP90 and mevalonate pathway components.
  • Assessment of STAT3 phosphorylation levels.

Main Results:

  • STAT3 inhibition reduced mutp53 expression by down-regulating HSP90 and mevalonate pathway molecules.
  • HSP90 and the mevalonate pathway were essential for sustaining STAT3 phosphorylation mediated by mutp53.

Conclusions:

  • Mutant p53 and STAT3 form a cooperative, cancer-promoting alliance.
  • This interaction involves HSP90 and the mevalonate pathway, offering potential therapeutic targets.
Keywords:
HSP90STAT3glioblastomamevalonate kinasemutp53pancreatic cancer

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