Modulatory Effects of IL-24 on Autophagy and Apoptosis in Large Cell Lung Carcinoma
TL;DR
It is validated that IL-24 exerts potent anti-cancer activity in primary LCLC by triggering excessive, toxic autophagy that drives past a cytoprotective survival threshold, successfully engaging the ATG4/ATG5 molecular switch to orchestrate a fatal transition into the intrinsic mitochondrial apoptotic pathway.
Abstract
Large cell lung carcinoma (LCLC) is a highly aggressive, undifferentiated subtype of non-small cell lung cancer characterized by rapid metastasis and resistance to traditional systemic chemotherapies. Targeted immunotherapies using cytokines like Interleukin-24 (IL-24) represent promising avenues to selectively induce cancer-specific cell death. This study evaluated the concentration-dependent cytotoxic and molecular modulatory effects of IL-24 on patient-derived primary LCLC cell lines. Primary LCLC cultures established from ultrasound-guided tru-cut biopsies were treated with varying concentrations of recombinant human IL-24 protein. Cell viability and growth inhibition rates were quantified using the MTT colorimetric assay. Transcriptional variations in the autophagic flux marker (LC3) and the initiator of intrinsic apoptosis (caspase-9) were evaluated using quantitative real-time PCR (RT-qPCR). MTT assay profiling demonstrated a strong concentration-dependent cytotoxic effect after 48 hours of treatment, yielding a half-maximal inhibitory concentration (IC50) of 22.9 pg/mL. Cell viability sharply collapsed from 82.5% at a sub-threshold dose of 5 pg/mL down to 14.7% at the maximum concentration of 100 pg/mL. RT-qPCR tracking showed a robust, dose-dependent upregulation of LC3 across all tested doses, indicating immediate activation of the autophagic pathway. Conversely, apoptotic response tracking revealed a distinct threshold activation; caspase-9 expression remained low at 10 pg/mL but co-elevated drastically with LC3 at higher concentrations of 50 pg/mL and 100 pg/mL. These findings validate that IL-24 exerts potent anti-cancer activity in primary LCLC by triggering excessive, toxic autophagy that drives past a cytoprotective survival threshold, successfully engaging the ATG4/ATG5 molecular switch to orchestrate a fatal transition into the intrinsic mitochondrial apoptotic pathway. Consistently supported by quantitative alignment between gene upregulation and loss of viability, IL-24 proves to be a compelling therapeutic candidate that warrants advanced in vivo evaluation.