Involvement of Aryl Hydrocarbon Receptor in L-Kynurenine-Mediated Parathyroid Hormone-Related Peptide Expression

Parathyroid hormone-related peptide (PTHrP), produced by specific cancers such as lung cancer, profoundly influences the formation of bone metastatic lesions via the "vicious cycle" of tumor growth and bone resorption. The changes in gene expression regulated by the abnormal microenvironment components play key roles in maintaining the biological characteristics of cells, such as the organotropism of cancer metastasis. A recent study has shown that L-kynurenine (L-Kyn), one of microenvironment components, induced a substantial increase in the metastasis of lung cancer cells. What remains unclear, however, is the linkage between L-Kyn and bone metastatic lesions. In the present paper, we found that a significant upregulation of PTHrP expression was detected when 95D cells, a lung cancer cell line, were incubated with 50 μM of L-Kyn. Meanwhile, L-Kyn (50/100 μM) strongly strengthened aryl hydrocarbon receptor (Ahr) expression. Additionally, L-Kyn (50 μM) increased the expression of the nuclear translocation of Ahr and cytochrome P450 1A1. Most importantly, the L-Kyn-induced upregulation of migration was significantly reduced when cells were co-incubated with siRNA_Ahr. Notably, the L-Kyn-mediated increase in PTHrP was also substantially attenuated upon siRNA_Ahr treatment in 95D cells. These results suggest that Ahr is involved in the L-Kyn-induced enhancement of PTHrP expression.