Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in MicroRNA expression

Leigh Ellis, Kristin Lehet, Swathi Ramakrishnan, Remi Adelaiye, Kiersten M. Miles, Dan Wang, Song Liu, Peter Atadja, Michael A Carducci, Roberto Pili

Research output: Contribution to journalArticle

Abstract

Specific inhibitors towards Histone Deacetylases (HDACs) and Mammalian Target of Rapamycin Complex 1 (mTORC1) have been developed and demonstrate potential as treatments for patients with advanced and/or metastatic and castrate resistant prostate cancer (PCa). Further, deregulation of HDAC expression and mTORC1 activity are documented in PCa and provide rational targets to create new therapeutic strategies to treat PCa. Here we report the use of the c-Myc adenocarcinoma cell line from the c-Myc transgenic mouse with prostate cancer to evaluate the in vitro and in vivo anti-tumor activity of the combination of the HDAC inhibitor panobinostat with the mTORC1 inhibitor everolimus. Panobinostat/everolimus combination treatment resulted in significantly greater antitumor activity in mice bearing androgen sensitive Myc-CaP and castrate resistant Myc-CaP tumors compared to single treatments. We identified that panobinostat/everolimus combination resulted in enhanced anti-tumor activity mediated by decreased tumor growth concurrent with augmentation of p21 and p27 expression and the attenuation of angiogenesis and tumor proliferation via androgen receptor, c-Myc and HIF-1α signaling. Also, we observed altered expression of microRNAs associated with these three transcription factors. Overall, our results demonstrate that low dose concurrent panobinostat/everolimus combination therapy is well tolerated and results in greater anti-tumor activity compared to single treatments in tumor bearing immuno-competent mice. Finally, our results suggest that response of selected miRs could be utilized to monitor panobinostat/everolimus in vivo activity.

Original languageEnglish (US)
Article numbere27178
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 7 2011

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Histone Deacetylases
Androgen Receptors
MicroRNAs
microRNA
histones
Tumors
hypoxia
prostatic neoplasms
neoplasms
Prostatic Neoplasms
Bearings (structural)
Neoplasms
mice
Therapeutics
therapeutics
Deregulation
androgens
angiogenesis
adenocarcinoma
Hypoxia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in MicroRNA expression. / Ellis, Leigh; Lehet, Kristin; Ramakrishnan, Swathi; Adelaiye, Remi; Miles, Kiersten M.; Wang, Dan; Liu, Song; Atadja, Peter; Carducci, Michael A; Pili, Roberto.

In: PLoS One, Vol. 6, No. 11, e27178, 07.11.2011.

Research output: Contribution to journalArticle

Ellis, Leigh ; Lehet, Kristin ; Ramakrishnan, Swathi ; Adelaiye, Remi ; Miles, Kiersten M. ; Wang, Dan ; Liu, Song ; Atadja, Peter ; Carducci, Michael A ; Pili, Roberto. / Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signaling associated with alterations in MicroRNA expression. In: PLoS One. 2011 ; Vol. 6, No. 11.
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