Journal
ONCOTARGET
Volume 8, Issue 41, Pages 70828-70840Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19993
Keywords
thailandepsin A; histone deacetylase inhibitor; neuroendocrine cancer; carcinoid; medullary thyroid cancer
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Funding
- Howard Hughes Medical Institute's Medical Research
- Young Supporters Board of the UAB Comprehensive Cancer Center New Faculty Development Award in Cancer Research
- Caring for Carcinoid Foundation-AACR
- American Cancer Society RS6
- American Cancer Society MEN2 Professorship
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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.-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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