KER 2569 Activation of the AhR leads to decreased apoptosis
Several studies have found that the activation of the AhR by stressors such as TCDD, can promote a decrease in apoptosis (KER1), which is a deleterious event with regards to cancer (Al-Dhfyan et al., 2017 Jan 19, Bekki et al., 2015). Additionally, an increase in cell death was found when blocking the AhR pathway using AhR silencing (RNA interference or knock-out), knockout cell lines or antagonists (CH223191 or alpha-naphthoflavone) (Goode et al., 2013 Dec 15, Al-Dhfyan et al., 2017 Jan 19, Bekki et al., 2015, Regan Anderson et al., 2018). The most frequently used assay to evaluate apoptosis was cytometry with the use of Annexin V: this was performed with ER-positive cells lines (MCF-7, T-47D), triple negative cell lines (MDA-MB-231, HS 578), cells over-expressing the Her2 (SK-BR-3) and cells lines derived from cancer samples from patients (Goode et al., 2013 Dec 15, Al-Dhfyan et al., 2017 Jan 19, Bekki et al., 2015, Regan Anderson et al., 2018, Fujisawa et al., 2011).
The concordance of the evidence was classified as “moderate” since the aim of most studies was to evaluate the capacity to survive in an apoptosis-promoting environment (i.e., chemotherapeutic drugs). Indeed, they assessed the resistance to chemotherapy agents such as doxorubicin and paclitaxel and found that the concomitant inactivation of the AhR pathway could decrease the resistance to these chemotherapy agents through an increase in cell death when compared to cells with a functional (or expressed at sufficient levels) AhR (Goode et al., 2013 Dec 15, Al-Dhfyan et al., 2017 Jan 19, Bekki et al., 2015, Regan Anderson et al., 2018, Fujisawa et al., 2011). Since the environment was modified by the presence of chemotherapy, the hypothesis of an alternative pathway cannot be completely discarded. It must be noticed that the exact biological mechanisms linking the activation of the AhR to the decrease in apoptosis remains unclear. Indeed, Anderson et al. suggested that the AhR interacts with the glucocorticoid receptor (GR) and the hypoxia inducible factor-2α (HIF-2α) (Regan Anderson et al., 2018). The presence of the GR is associated with a poor prognosis, notably in triple negative breast cancer (Pan et al., 2011, Moran et al., 2000 Feb 15). Indeed, this receptor is involved in survival and resistance to chemotherapy through up-regulation of c-myc, Bcl2 and Kruppel-like factor 5 (Pan et al., 2011, Wu et al., 2004, Li et al., 2017). Both GR and HIF 2α could be up regulated by the AhR. They then activate Brk (also known as PTK6), a ligand of EGFR (epidermal growth factor receptor), involved in the inhibition of apoptosis (Regan Anderson et al., 2018, Li et al., 2012). Another possible mechanism suggested by Bekki et al. is that the decrease in apoptosis was caused by the induction of cyclooxygenase 2 (COX-2) and the NF-κB subunit RelB (Bekki et al., 2015). They both prevent apoptosis through induction of Bcl2, an anti-apoptotic factor (Tsujii and DuBois, 1995, Vogel et al., 2007, Thomas et al., 2020, Baud and Jacque, 2008 Dec, Demicco et al., 2005 Nov, Wang et al., 2007 Apr, Liu et al., 2001 May 25).