Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation

Antioxidants & Redox Signaling
Yuan-ming PanYou-yong Lü

Abstract

Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-κB) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IκB-α in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-κB in GC cells. DATS attenuated NF-κB signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IκB-α to suppress NF-κB activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-κB inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumor...Continue Reading

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Methods Mentioned

BETA
xenograft
FACS
electrophoretic mobility shift assay
ChIP
PCR
immunoprecipitation
histone acetylation
transfection
xenografts
biopsy

Software Mentioned

SPSS

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