Caspase-4 promotes both metastasis and interferon-γ-induced cell death in non-small cell lung cancer

Abstract Caspase-4 (CASP4) is a member of the inflammatory caspase subfamily and promotes inflammation. Here, we report that CASP4 in non-small cell lung cancer cells contributes to both tumor progression via angiogenesis and tumor hyperkinesis and tumor cell killing in response to high interferon (IFN)-γ levels. We revealed that elevated CASP4 expression within the primary tumor was associated with cancer progression in patients with non-small cell lung cancer. Further, CASP4 knockout attenuated tumor angiogenesis and metastasis in syngeneic mouse models. CASP4 enhanced the expression of genes associated with angiogenesis and cell migration through nuclear factor kappa-light chain-enhancer of activated B cell signaling without lipopolysaccharide or tumor necrosis factor in lung cancer cell lines. CASP4 was induced by endoplasmic reticulum stress or IFN-γ via signal transducer and activator of transcription 1. Most notably, lung cancer cells with high CASP4 expression were more prone to IFN-γ-induced cell death than those with low CASP4 expression. Our findings indicate that the CASP4 level in primary non-small cell lung cancer can predict metastasis and responsiveness to high-level IFN-γ therapy.