Title:Trailing TRAIL Resistance in Human Breast Adenocarcinoma Cells with Trichostatin
A and Zebularine
Volume: 23
Issue: 7
Author(s): Sonia How Ming Wong, Chee-Mun Fang, Hwei-San Loh and Siew Ching Ngai*
Affiliation:
- School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia
Keywords:
TRAIL, trichostatin A, zebularine, apoptosis, breast cancer, resistance.
Abstract:
Aims: The aim of this study was to sensitize the resistant breast adenocarcinoma cells towards Tumour
Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced apoptosis.
Background: Breast cancer is a heterogeneous disease involving complex mechanisms. TRAIL is a potential anticancer
candidate for targeted treatment due to its selective killing effects on neoplastic cells. Nonetheless, resistance
occurs in many cancers either intrinsically or after multiple treatments.
Objective: Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb)
(TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis.
Methods: The breast adenocarcinoma cells, MDA-MB-231, MCF-7 and E-MDA-MB-231 (E-cadherin re-expressed
MDA-MB-231) were treated with TSA, Zeb, TZ, TRAIL and TZT. The cells were subjected to hematoxylin and eosin
(H & E) staining and FITC-Annexin V/Propidium Iodide apoptosis detection prior to proteome profiling.
Results: Based on morphological observation, apoptosis was induced in all cells treated with all treatment regimens
though it was more evident for the TZT-treated cells. In the apoptosis detection analysis, TZ increased early apoptosis
significantly in MDA-MB-231 and MCF-7 while TRAIL induced late apoptosis significantly in E-MDA-MB-231.
Based on the proteome profiling on MDA-MB-231, TRAIL R2 and Fas expression was increased. For E-MDA-MB-
231, down-regulation of catalase, paraoxonase-2 (PON2), clusterin, an inhibitor of apoptosis proteins (IAPs) and cell
stress proteins validated the notion that E-cadherin re-expression enhances TZT anti-cancer efficacy. Similar trend was
observed in MCF-7 whereby TZT treatment down-regulated the anti-apoptotic catalase and PON2, increased the proapoptotic,
B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax), second
mitochondria-derived activator of caspase (SMAC) and HtrA serine peptidase 2 (HTRA2) as well as TRAIL receptors
(TRAIL R1 and TRAIL R2).
Conclusion: TZ treatment serves as an efficient treatment regimen for MDA-MB-231 and MCF-7, while TRAIL
serves as a better treatment option for E-MDA-MB-231. Therefore, future studies on E-cadherin’s positive regulatory
role in TRAIL-induced apoptosis are warranted.