Influence of the HDAC inhibitor Valproic acid on the growth and proliferation of Temsirolimus-resistant prostate cancer cells in vitro

  • The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens.

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Author:Jasmina Makarević, Jochen RutzGND, Eva JüngelORCiDGND, Sebastian Maxeiner, Igor TsaurORCiDGND, Felix ChunORCiDGND, Jürgen Bereiter-HahnORCiDGND, Roman A. BlahetaORCiD
Pubmed Id:
Parent Title (English):Cancers
Place of publication:Basel
Contributor(s):Karen Nelson
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/04/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/29
Tag:HDAC; cdk; cell growth; cyclins; mtor; prostate cancer; resistance; temsirolimus; valproic acid
Issue:4, Art. 566
Page Number:14
First Page:1
Last Page:14
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
Institutes:Biowissenschaften / Biowissenschaften
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0