Aryl Hydrocarbon Receptor Suppresses the Prostate Cancer LNCaP Cell Growth and Invasion by Promoting DNA Damage Response Under Oxidative Stress

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that interacts with multiple signaling pathways during prostate development. In the present study, LNCaP cells were knocked down of AhR by siRNA, or treated with the AhR agonist 3-methylcholanthrene (3MC). The effects of AhR on LNCaP cells and the associated mechanisms were studied both under normal condition and under hydrogen peroxide (HO)induced oxidative stress. MTT, transwell chamber assays and flow cytometry were employed to investigate cell proliferation, invasion, and apoptosis, respectively, whereas the DNA damage response (DDR) signaling (phosphorylation of ataxia-telangiectasia mutated [ATM], check-point kinase 2 [Chk2], histone H2AX, p53, and cleaved poly-ADP-ribose polymerase [PARP]) was detected by western blotting. Exposure of LNCaP cells to HO inhibited their viability and migration, and induced apoptosis, at a greater extent compared with the culture under normal conditions. In addition, the oxidative stress increased p-ATM, p-Chk2, p-p53, and p-H2AX expression levels significantly. Knockdown of AhR attenuated the aforementioned effects caused by HO-induced oxidative stress. Activation of AhR by 3MC treatment, further aggravated these changes of LNCaP cells on oxidative stress. The findings indicated that AhR suppresses the viability and migration of LNCaP cells notably under oxidative stress, and this process is associated with positive regulation of the responses to oxidative DNA damage.

RAB3D, upregulated by aryl hydrocarbon receptor (AhR), promotes the progression of prostate cancer by activating the PI3K/AKT signaling pathway

“…(Al-Dhfyan et al, 2017;Baker & Sakoff, 2020;Donovan et al, 2018;Guarnieri, 2020;Peng et al, 2009;Tsay et al, 2013). Consistent with these findings, in our previous studies, we found that AhR aggravates the PCa progression (Yu et al, 2017(Yu et al, , 2018.…”

Differentially Expressed Genes and Molecular Pathways in an Autochthonous Mouse Prostate Cancer Model

“…The top ranked overrepresented pathway [-log( p -value 5.19)] includes the Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that interacts with multiple signaling pathways during prostate development. AHR suppresses the viability and migration of human prostate cancer LNCaP cells (Yu et al, 2017), and plays pivotal role in cancer by modulating the downstream expression of Mitogen-Activated Protein Kinase Kinase Kinase 12 (MAP3K12) (Yu et al, 2018). AHR plays an important role in cellular homeostasis and disease development, and the Aryl hydrocarbon receptor nuclear translocator (AHRN) forms a complex with ligand bound AHR during cancer and activates Bax, a central cell death regulator, MAPK, Aldehyde dehydrogenases (ALDHs), Glutathione transferase (GST) and others (Supplemental Figure 1).…”

The Role of Geomagnetic Field Intensity in Late Quaternary Evolution of Humans and Large Mammals

“…The process initiates apoptosis and involves damage to nuclear DNA accompanied by mitochondrial dysfunction 10.1029/2018RG000629 (Frauenstein et al, 2013). There is a general consensus that the AhR of modern humans is implicated in DNA repair (Dittmann et al, 2016;Schreck et al, 2009), tumor suppression (Fan et al, 2010;Yu et al, 2017), epidermal barrier function (Noakes, 2015), skin tanning response, and melanocyte homeostasis (Jux et al, 2011;Luecke et al, 2010). Phylogenetic analysis suggested that the ability of vertebrate AhR to sense xenobiotics was acquired at a late stage of evolution, implying that the driving force for evolutionary conservation of AhR lies not only in its role in xenobiotic metabolism but also in normal cell development (Hahn et al, 2017;Hao & Whitelaw, 2013).…”