Aryl Hydrocarbon Receptor Promotes Cell Growth, Stemness Like Characteristics, and Metastasis in Human Ovarian Cancer via Activation of PI3K/Akt, β-Catenin, and Epithelial to Mesenchymal Transition Pathways

Abstract

Ovarian cancer (OC) ranks first in cancer-related deaths out of all female reproductive malignancies with high-pitched tumor relapse and chemoresistance. Several reports correlate cancer occurrences with exposure to xenobiotics via induction of a protein receptor named aryl hydrocarbon receptor (AhR). However, the effect of AhR on OC proliferation, expansion, and chemoresistance remains unrevealed. For this purpose, OC cells A2780 and A2780cis cells were treated with AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the effects were determined by Real-Time Cell Analyzer, clonogenic assay, flow cytometry, immunoblotting and wound healing assay. Our results showed that activation of AhR by TCDD in A2780 cells induced the PI3K/AKT pathway followed by induction of anti-apoptotic proteins BCL-2, BCL-xl, and MCL-1. In addition, a significant increase in stemness marker aldehyde dehydrogenase (ALDH1) was observed. This effect was also associated with an accumulation of β-catenin, a Wnt transcription factor. Moreover, we observed induction of epithelial to mesenchymal transition (EMT) upon AhR activation. In conclusion, the results from the current study confirm that AhR mediates OC progression, stemness characteristics, and metastatic potential via activation of PI3K/Akt, Wnt/β-catenin, and EMT. This study provides a better insight into the modulatory role of AhR that might help in developing novel therapeutic strategies for OC treatment.

Crosstalk between aryl hydrocarbon receptor (AhR) and BCL-2 pathways suggests the use of AhR antagonist to maintain normal differentiation state of mammary epithelial cells during BCL-2 inhibition therapy

“…Interestingly, BCL-2 protein showed the highest inducible protein in response to the AhR inducer linked to cancer proliferation and cell cycle. Similar results from our laboratory have shown that TCDD induces several anti-apoptotic proteins such as BCL-xl and MCL-1 in ovarian cancer cell lines [37] .…”

Role of RAS signaling in ovarian cancer

“…153 Though our group has already reported the involvement of AhR in inducing tumor proliferation in OC, the cross-talk between AhR and the RAS pathway still needs to be investigated thoroughly. 154 TCDD, an AhR activator, is found to induce RAS activity in hepatoma cells; however, studies contradict each other in terms of tissue specificity of this cross-talk. [155][156][157] Moreover, a microarray global expression analysis report has shown that RAS MAP kinase pathway activation observed in TCDD-treated human hepatoma cells to be AhR-dependent.…”

Unlocking the secrets: exploring the influence of the aryl hydrocarbon receptor and microbiome on cancer development

“…In support of the role of AhR in cancer development, researchers have identified upregulated expression of AhR in human and rodent tumors, such as breast cancer [ 125 – 127 ], lung adenocarcinoma [ 128 , 129 ], and ovarian cancer [ 130 ], implicating the role of AhR in tumor progression. Interestingly, AhR also holds a functional role in the molecular mechanisms governing the development of CSCs, which are well-known tumor-initiating cells, along with being targets for several chemical carcinogens.…”