Our previous study has demonstrated that two low molecular weight-polycyclic aromatic hydrocarbons (LMW-PAHs), phenanthrene (Phe) and fluorene (Flu), alone and as a mixture could induce oxidative damage and inflammation in A549 cells. However, the associated mechanisms have not been well discussed. The aim of this study was to further investigate the roles of PI3K/AKT and NF-κB signaling pathways in the inflammatory effects in A549 cells induced by Phe, Flu and their mixture. The results indicated that Phe, Flu and their mixture significantly activated PI3K/AKT and NF-κB signaling pathways by increasing the phosphorylation levels of PI3K, AKT, IκBα and NF-κB p65. In addition, pro-inflammatory cytokine expressions of TNF-α and IL-6 induced by the binary mixture of Phe and Flu were all alleviated by co-treatment with PI3K/AKT and NF-κB specific inhibitors (LY294002 and BAY11-7082). The results suggested that PI3K/AKT and NF-κB signaling pathways played an important role in LMW-PAHs induced inflammation in A549 cells.

Parkin is a well-established synergistic mediator of mitophagy in dysfunctional mitochondria. Mitochondria are the main target of arsenic trioxide (ATO) cytotoxicity, and the effect of mitophagy on ATO action remains unclear. In this study, we used stable Parkin-expressing (YFP-Parkin) and Parkin loss-of-function mutant (Parkin C431S) HeLa cell models to ascertain whether Parkin-mediated mitophagy participates in ATO-induced apoptosis/cell death. Our data showed that the overexpression of Parkin significantly sensitized HeLa cells to ATO-initiated proliferation inhibition and apoptosis; however, the mutation of Parkin C431S significantly weakened this Parkin-mediated responsiveness. Our further investigation found that ATO significantly downregulated two fusion proteins (Mfn1/2) and upregulated fission-related protein (Drp1). Autophagy was also activated as evidenced by the formation of autophagic vacuoles and mitophagosomes, increased expression of PINK1, and recruitment of Parkin to impaired mitochondria followed by their degradation, accompanied by the increased transformation of LC3-I to LC3-II, increased expression of Beclin1 and decreased expression of P62 in YFP-Parkin HeLa cells. Enhanced mitochondrial fragmentation and autophagy indicated that mitophagy was activated. Furthermore, during the process of mitophagy, the overproduction of ROS implied that ROS might represent a key factor that initiates mitophagy following Parkin recruitment to mitochondria. In conclusion, our findings indicate that Parkin is critically involved in ATO-triggered mitophagy and functions as a potential antiproliferative target in cancer cells.