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Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

1
Department of Urology, Goethe-University, D-60590 Frankfurt am Main, Germany
2
Institute for Cell Biology and Neurosciences, Goethe-University, D-60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Current address: Department of Urology and Pediatric Urology, University Medical Center Mainz, 55131 Mainz, Germany.
Cancers 2019, 11(4), 566; https://doi.org/10.3390/cancers11040566
Received: 1 April 2019 / Accepted: 16 April 2019 / Published: 19 April 2019
(This article belongs to the Collection Histone Modification in Cancer)
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Abstract

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. View Full-Text
Keywords: mtor; HDAC; cell growth; cdk; cyclins; prostate cancer; resistance; valproic acid; temsirolimus mtor; HDAC; cell growth; cdk; cyclins; prostate cancer; resistance; valproic acid; temsirolimus
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Makarević, J.; Rutz, J.; Juengel, E.; Maxeiner, S.; Tsaur, I.; Chun, F. .-H.; Bereiter-Hahn, J.; Blaheta, R.A. Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro. Cancers 2019, 11, 566.

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