Oncotarget

Research Papers:

Histone deacetylase inhibitor thailandepsin-A activates Notch signaling and suppresses neuroendocrine cancer cell growth in vivo

Samuel Jang, Andrew Janssen, Zviadi Aburjania, Matthew B. Robers, April Harrison, Ajitha Dammalapati, Yi-Qiang Cheng, Herbert Chen and Renata Jaskula-Sztul _

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Oncotarget. 2017; 8:70828-70840. https://doi.org/10.18632/oncotarget.19993

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Abstract

Samuel Jang1,2, Andrew Janssen2, Zviadi Aburjania2, Matthew B. Robers3, April Harrison2, Ajitha Dammalapati2, Yi-Qiang Cheng4, Herbert Chen2 and Renata Jaskula-Sztul2

1Howard Hughes Medical Institute, Birmingham, AL, USA

2Department of Surgery, School of Medicine, University of Alabama, Birmingham, AL, USA

3Promega Corporation, Fitchburg, WI, USA

4UNT System College of Pharmacy, Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA

Correspondence to:

Renata Jaskula-Sztul, email: [email protected]

Keywords: thailandepsin A, histone deacetylase inhibitor, neuroendocrine cancer, carcinoid, medullary thyroid cancer

Received: June 20, 2017    Accepted: July 23, 2017    Published: August 07, 2017

ABSTRACT

Novel therapies for neuroendocrine (NE) cancers are desperately needed as they frequently present as metastatic disease and cause debilitating symptoms by secreting excessive hormones. Induction of Notch isoforms has a tumor suppressive effect in NE cancer cell lines, and we have observed that histone deacetylase inhibitors (HDACi) potently activate Notch. In this study, we describe the potential for Burkholderia thailandensis-derived class I HDACi thailandepsin A (TDP-A) as a Notch activator and therapeutic agent against NE cancer. IC50 for TDP-A was determined to be 4-6 nM in NE cancer cell lines (BON, MZ-CRC-1, and TT) without cytotoxicity to lung fibroblasts. The binding characteristics of TDP-A to its target HDAC1 was examined using bioluminescence resonance energy transfer (BRET). Western blot and flow cytometry analysis showed that TDP-A induces cell cycle arrest and apoptosis in a dose-dependent manner. TDP-A dose-dependently activated the Notch pathway as measured by increasing functional CBF1-luciferase reporter signal and mRNA and protein expressions of Notch isoforms, which were attenuated by pretreatment with γ-secretase inhibitor DAPT. Furthermore, TDP-A lead to changes in expression level of downstream targets of Notch pathway and reduced expression of NE cancer markers. An in vivo study demonstrated that TDP-A suppressed NE cancer progression. These results show that TDP-A, as a Notch activator, is a promising agent against NE cancers.


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