Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis

Abstract

In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[a]pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by β-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure.

Sensitization of Human Liver Cells Toward Fas‐Mediated Apoptosis by the Metabolically Activated Pyrrolizidine Alkaloid Lasiocarpine

“…A comparable mechanism of xenobiotic‐induced sensitization toward Fas‐mediated apoptosis was observed earlier for benzo[ a ]pyrene in HaCaT cells . Stolpmann et al showed the induction of Fas‐mediated apoptosis by benzo[ a ]pyrene at concentrations activating the aryl hydrocarbon receptor .…”

“…A comparable mechanism of xenobiotic‐induced sensitization toward Fas‐mediated apoptosis was observed earlier for benzo[ a ]pyrene in HaCaT cells . Stolpmann et al showed the induction of Fas‐mediated apoptosis by benzo[ a ]pyrene at concentrations activating the aryl hydrocarbon receptor . Furthermore, the phenomenon of sensitization toward Fas‐mediated apoptosis was observed in different carcinoma cell lines after treatment with anticancer drugs like cisplatin and doxorubicin .…”

Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective

“…46 However, other in vitro reports showed that exposure to BaP or its DNA-reactive metabolite anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) induces or sensitizes human cells to either receptormediated or mitochondrial-mediated apoptosis. 47,48 Similar results were obtained using a reverse phase protein array comparing mouse primary liver tumours induced by BaP to their normal adjacent tissues. 49 The results showed both downregulation (eg cleaved caspase 7, caspase 3) and upregulation (Bax, Bad and Bcl-xL) of some pro-apoptotic proteins in tumour tissues.…”

Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism

“…Besides, B[a]P has been found to sensitize human keratinocytes for the apoptosis induced by the Fas ligand or the cytokine TRAIL via an AhR-dependent potentiation of caspase-8 activity [101]. With respect to the B[a]P-induced necrosis/necroptosis, in addition to a possible involvement of some Bcl-2 family members [90,91], it has been shown that ROS production and lipid peroxidation [95] as well as PARP-1, an enzyme involved in DNA repair [94], would also play a role.…”