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Background Cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcomes. In this study, we established two highly invasive lung cancer cell models (A549-i8 and H1299-i8) and identified mesoderm-specific transcript (MEST) as a novel invasive regulator of lung cancer. We aim to characterize its biological function and clinical significance in lung cancer metastasis. Methods Transwell invasion assay was performed to establish high-invasive lung cancer cell model. Immunohistochemistry (IHC) was used to detect MEST expression in tumor tissues. Mass spectrometry and bioinformatic analyses were used to identify MEST-regulated proteins and binding partners. Co-immunoprecipitation assay was performed to detect the interaction of MEST and VCP. The biological functions of MEST were investigated in vitro and in vivo. Immunofluorescence staining was conducted to explore the colocalization of MEST and VCP. Results MEST overexpression promoted metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST increased the interaction between VCP and IκBα, which accelerated IκBα degradation and NF-κB activation. Such acceleration was abrogated by VCP silencing, indicating that MEST is an upstream activator of the VCP/IκBα/NF-κB signaling pathway. Furthermore, high expressions of MEST and VCP were associated with poor survival of lung cancer patients. Conclusion Collectively, these results demonstrate that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP to coordinate the IκBα/NF-κB pathway. Targeting the MEST/VCP/IκBα/NF-κB signaling pathway may be a promising strategy to treat lung cancer.

Resistance to tumor‐necrosis‐factor‐related apoptosis‐inducing ligand (TRAIL) of cancer cell remains a key obstacle for clinical cancer therapies. To overcome TRAIL resistance, this study identifies curcumol as a novel safe sensitizer from a food‐source compound library, which exhibits synergistic lethal effects in combination with TRAIL on non‐small cell lung cancer (NSCLC). SILAC‐based cellular thermal shift profiling identifies NRH:quinone oxidoreductase 2 (NQO2) as the key target of curcumol. Mechanistically, curcumol directly targets NQO2 to cause reactive oxygen species (ROS) generation, which triggers endoplasmic reticulum (ER) stress‐C/EBP homologous protein (CHOP) death receptor (DR5) signaling, sensitizing NSCLC cell to TRAIL‐induced apoptosis. Molecular docking analysis and surface plasmon resonance assay demonstrate that Phe178 in NQO2 is a critical site for curcumol binding. Mutation of Phe178 completely abolishes the function of NQO2 and augments the TRAIL sensitization. This study characterizes the functional role of NQO2 in TRAIL resistance and the sensitizing function of curcumol by directly targeting NQO2, highlighting the potential of using curcumol as an NQO2 inhibitor for clinical treatment of TRAIL‐resistant cancers., This study discovered that curcumol sensitizes lung cancer cell to tumor‐necrosis‐factor‐related apoptosis‐inducing ligand (TRAIL)‐mediated apoptosis. Curcumol exhibits synergistic lethal effects with TRAIL on cancer cell by directly targeting quinone oxidoreductase 2 (NQO2) to induce reactive oxygen species, triggering ER stress‐C/EBP homologous protein (CHOP)‐death receptor 5 (DR5) signaling to combat TRAIL‐resistant cancer.