Parthenolide sensitizes ultraviolet (UV)-B-induced apoptosis via protein kinase C-dependent pathways

Abstract

Parthenolide (PN) is the principal sesquiterpene lactone in feverfew (Tanacetum parthenium) with proven anti-inflammatory properties. We have previously reported that PN possesses strong anticancer activity in ultraviolet B (UVB)-induced skin cancer in SKH-1 hairless mice. In order to further understand the mechanism(s) involved in the anticancer activity of PN, we investigated the role of protein kinase C (PKC) in the sensitization activity of PN on UVB-induced apoptosis. Several subtypes of PKC have been reported to be involved in UVB-induced signaling cascade with both pro- and anti-apoptotic activities. Here we focused on two isoforms of PKC: novel PKCdelta and atypical PKCzeta. In JB6 murine epidermal cells, UVB induces the membrane translocations of both PKCs, and PN pre-treatment enhances the membrane translocation of PKCdelta, but inhibits the translocation of PKCzeta. Similar results were also detected when the activities of these PKCs were tested with the PKC kinase assay. Moreover, pre-treatment with a specific PKCdelta inhibitor, rotterlin, completely diminishes the sensitization effect of PN on UVB-induced apoptosis. When cells were transiently transfected with dominant negative PKCdelta or wild-type PKCzeta, the sensitization effect of PN on UVB-induced apoptosis was also drastically reduced. Further mechanistic study revealed that PKCzeta, but not PKCdelta, is required for UVB-induced p38 MAPK activation and PN is likely to act through PKCzeta to suppress p38 activation in UVB-treated JB6 cells. In conclusion, we demonstrated that PN sensitizes UVB-induced apoptosis via PKC-dependent pathways.

GSK3β signaling is involved in ultraviolet B-induced activation of autophagy in epidermal cells

“…UVB causes apoptosis in JB6 cells through complex mechanisms; it may be mediated by oxidative stress, PKC, or a p53-dependent manner (12,43,44). The signaling pathways for UVB-mediated autophagy and apoptosis may or may not overlap.…”

“…JB6 cells have been extensively used to study the mechanisms of epidermal cell transformation (9–11). UVB causes the death of JB6 cells in the form of apoptosis (12). We demonstrated that UVB activated autophagy in JB6 cells, and autophagy appeared to be a protective response to UVB-induced damage.…”

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

“…We observed that the pan-PKC inhibitor GF109203X suppressed ERK and p38 activation and apoptosis induced by 4HPR, suggesting that PKC may be an upstream regulator of ERK in our system. Others have reported that PKCdelta is upstream of changes in mitochondrial memebrane leading to cytochrome c release (Liao et al, 2005) and PKCzeta is upstream of p38 MAPK activation in UVB-induced apoptosis (Won et al, 2005). ROS may be upstream of PKC because it has been shown that PKC-dependent induction of p21WAF1 by phorbol ester was inhibited by antioxidant (Traore et al, 2005).…”

High glucose suppresses expression of equilibrative nucleoside transporter 1 (ENT1) in rat cardiac fibroblasts through a mechanism dependent on PKC‐ζ and MAP kinases

“…This indicates that high glucose suppresses expression of ENT1 in CFs by activating PKC‐ζ and both ERK1/2 and p38 MAPK signaling pathways. It has been already demonstrated that PKC‐ζ has the ability to activate both the Raf‐1/MEK/ERK1/2 cascade (Berra et al, 1995) and p38 MAPK (Buteau et al, 2001; Won et al, 2005). However, simultaneous activation of ERK1/2 and p38 MAPK pathways in the same cell is relatively rare occurrence.…”