Arsenic-induced circFNDC3B regulates apoptosis through dysregulation of NF-κB Signaling

Arsenic is a widely distributed environmental toxicant that significantly increases the risk of developing multiple tumors. Limited information is available, however, on whether arsenic can regulate circFNDC3B to exert its toxicological responses. We provide evidence herein that circFNDC3B expression was upregulated in a dose-dependent manner in A549 cells treated with sodium arsenite. Silencing circFNDC3B suppressed A549 cell proliferation and induced Apoptosis. We then examined the protein levels of key proliferation-and apoptosis-related genes within the NF-κB and p53 pathways following circFNDC3B silencing. Results demonstrated that silencing circFNDC3B significantly elevated total p53 protein levels, but reduced phosphorylation at Ser392/Ser315 and downregulation of key downstream effectors (MDM2, Bak, Bax, PUMA, p21). Critically, circFNDC3B silencing dramatically reduced the interaction between IKKβ and the NF-κB subunit p65. This impaired binding directly disrupted canonical NF-κB signaling, as evidenced by markedly diminished phosphorylation of p65 and IκBα, along with significantly decreased the expressions of downstream NF-κB target genes. These genes included pivotal anti-apoptotic factors (Bcl-2, XIAP, cIAP1, cIAP2, FLIP) and cell cycle regulators (Cyclin D1, PCNA). In conclusion, arsenic induced circFNDC3B expression, and circFNDC3B acted as anti-apoptotic and pro-survival effects through dysregulation of NF-κB pathways, potentially serving as a novel therapeutic target in lung Cancer.

NF-κB P65 signal pathway; apoptosis; arsenic; circFNDC3B.