Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells

Abstract

The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.

CD44/PI3K/NF-κB/AHR is a Novel Signaling Pathway Mediating Breast Tumor Progression

“…Previous studies have linked directly or indirectly AHR with CD44 signaling associated with cancer cell proliferation, migration and invasion [17][18][19][20]. In fact, many studies have shown that AHR can promote cell growth and survival of various tumor cells.…”

“…In fact, many studies have shown that AHR can promote cell growth and survival of various tumor cells. AHR knockout cells showed a decreased proliferation rate, accompanied by altered cell cycle progression [20]. Loss of AHR was linked to inhibition of the expression and/or activity of the components of the PI3K/Akt signaling pathway [20].…”

“…AHR knockout cells showed a decreased proliferation rate, accompanied by altered cell cycle progression [20]. Loss of AHR was linked to inhibition of the expression and/or activity of the components of the PI3K/Akt signaling pathway [20]. Findings from the literature have already established that tumor cells evolve, invariably, a sustained PI3K/Akt signaling as an effective mechanism to evade apoptosis and maintain cell survival [20; 22].…”

“…To further increase our understanding of the underlying CD44-downstream signaling pathways involved in BC metastasis, we analysed our CD44-CHIP microarray and selected aryl hydrocarbon receptor (AHR) for validation as an additional potential target gene of CD44 [11]. AHR is a ligand-activated transcription factor that plays an important role in various biological activities and tumorigenesis [16][17][18][19][20]. In this study, we have designed both in vitro and ex-vivo experiments to test the hypothesis and validate AHR as a true transcriptional target of CD44-downstream signaling promoting BC cell invasion.…”

Aryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey

“…Deletion of AhR enhances the invasive capacity of the MDA-MB-231 breast cancer cells, but on the contrary decreases cell proliferation and proliferation-related genes [ 70 ]. Furthermore, deletion of AhR in the colon cancer cells HCT116 and HT29 represses proliferation in a cell-specific manner [ 71 ]. This was concomitant with altered cell cycle progression, decreased ATP production, suppression of fatty acids biosynthetic pathway, and reduced expression and/or activity of the components of the PI3K/AKT pathway [ 71 ].…”