Furanodienone induces apoptosis via regulating the PRDX1/MAPKs/p53/caspases signaling axis through NOX4-derived mitochondrial ROS in colorectal cancer cells.

Furanodienone, a biologically active constituent of sesquiterpenes isolated from Rhizome Curcumae, has been reported to induce apoptosis in human colorectal cancer (CRC) cells by promoting the generation of reactive oxygen species (ROS). However, the source of ROS and how it manipulates apoptosis in CRC cells remains to be elucidated. Herein, we assessed the potential role of the well-known sources of intracellular ROS-mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate oxidases (NOXs), on furanodienone-induced cell death. The results indicated that furanodienone substantially increased the levels of mitochondrial ROS, which were subsequently eliminated by the general NOX inhibitor. Specifically, the nuclear factor kappa-B (NF-κB) translocation triggered a significant rise in the expression of NOX4, an isoform of the NOXs family, upon furanodienone treatment. Nevertheless, the specific NOX4 inhibitor GLX351322 attenuated cell apoptosis and mitochondrial ROS production. As a result, ROS burst induced by furanodienone suppressed the expression of peroxiredoxin1 (PRDX1), a redox signaling protein overexpressed in CRC cells, through a nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent pathway, thus amplifying the mitogen-activated protein kinases (MAPKs)/p53-mediated apoptotic signaling by increasing the p-p38, p-JNK levels, as well as the cleaved caspases -3, -8 and -9. In vivo experiments further confirmed the anti-proliferative impact of PRDX1 following furanodienone treatment. In summary, the study demonstrated that furanodienone-induced apoptosis in CRC cells is initiated by mitochondrial ROS derived from NOX4, which targeted the PRDX1 and activated the downstream MAPKs/p53-mediated caspase-dependent signaling pathway. Our findings may provide novel insights into the development of adjuvant drugs for CRC treatment and therapeutic applications.