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Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate

Jasmina Makarević1, Jochen Rutz2, Eva Juengel3

  • 1Department of Urology, Goethe-University, D-60590 Frankfurt am Main, Germany. jmakarevic@air-net.de.

Cancers
|April 24, 2019
PubMed

Insights

Valproic acid (VPA), a histone deacetylase inhibitor, counteracts resistance to temsirolimus, an mTOR inhibitor, in prostate cancer cells. VPA reduces tumor cell growth by down-regulating key cell cycle proteins and mTOR signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Mechanistic target of rapamycin (mTOR) is elevated in prostate cancer (PCa), presenting a therapeutic target.
  • Resistance to mTOR inhibitors like temsirolimus is a significant clinical challenge in PCa treatment.
  • Epigenetic modifications, such as histone acetylation, play a role in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate if valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, can overcome temsirolimus resistance in PCa cells.
  • To elucidate the molecular mechanisms by which VPA affects cell cycle progression and signaling pathways in resistant PCa cells.

Main Methods:

  • Prostate cancer cell lines, both sensitive and resistant to temsirolimus, were treated with VPA.
  • Cell proliferation, clonal growth, and cell cycle distribution were analyzed.
  • Expression and activity of key cell cycle proteins (cdk1, cyclin B, p19, p21, p27) and signaling molecules (Akt, mTOR, Raptor, Rictor) were assessed.
  • Histone acetylation levels were measured.
  • Gene knockdown of specific proteins was performed to assess their role in VPA's effects.

Main Results:

  • Temsirolimus-resistant PCa cells exhibited increased G2/M phase population, proliferation, and clonal growth.
  • VPA treatment significantly reduced cell growth in resistant PCa cells and increased histone H3 and H4 acetylation.
  • VPA decreased cdk1, cyclin B, phosphorylated mTOR, and Raptor levels.
  • VPA increased Rictor and phosphorylated Akt levels.
  • Knockdown of cdk1, cyclin B, or Raptor mimicked the growth-inhibitory effects of VPA.

Conclusions:

  • HDAC inhibition by VPA effectively counteracts temsirolimus resistance in PCa cells, likely through down-regulation of cdk1, cyclin B, and Raptor.
  • The observed increase in Rictor and Akt upon VPA treatment may indicate an adaptive feedback loop that warrants consideration in therapeutic strategy design.
Keywords:
HDACcdkcell growthcyclinsmtorprostate cancerresistancetemsirolimusvalproic acid

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