The induction of NF-E2-related factor-2 (Nrf2)-mediated detoxifying/
antioxidant enzymes is recognized as an effective strategy for
cancer chemoprevention. Here, we report that
3-morpholinopropyl isothiocyanate (3MP-ITC) is an exceptionally strong chemical inducer of these
enzymes. Exposure of
3MP-ITC in HepG2C8 cells not only induced endogenous Nrf2
protein but also suppressed endogenous
Kelch-like ECH-associated protein 1, resulting in an increased nuclear accumulation of Nrf2. Using chemical inhibitors of
protein synthesis (
cycloheximide) and 26S proteosomal degradation (MG-132), we observed that the induction of Nrf2
protein by
3MP-ITC appeared to be post-translationally regulated.
3MP-ITC activated ERK1/2 and JNK1/2 and the activation of antioxidant response element (ARE) by
3MP-ITC was significantly attenuated by chemical inhibition of PKC and PI3K signaling pathways in HepG2C8 cells. Treatment with
3MP-ITC significantly depleted the intracellular level of
glutathione (GSH) in HepG2C8 cells and
oral administration of
3MP-ITC increased the
protein expression of hepatic
NAD[P]H:
quinone oxidoreductase-1 and Nrf2 in Nrf2 (+/+) but not in Nrf2 (-/-) mice, whereas
UDP-glucuronosyl
transferase 1A1 was induced in both genotypes. Our results indicate that
3MP-ITC is a novel ITC that strongly induces Nrf2-dependent ARE-mediated detoxifying/
antioxidant enzymes in vitro and in vivo via the Nrf2 signaling pathway coupled with GSH depletion and activation of multiple signaling
kinase pathways, which could be potentially useful agent for
cancer chemoprevention.