MCOLN1 ‐Mediated Endoplasmic Reticulum Stress Induces Autophagy to Facilitate Lung Cancer Growth, Migration, and Invasion

ABSTRACT Autophagy is a highly conserved cellular degradation process that stimulates tumor cell migration and invasion. Moreover, MCOLN1 has already been proven to be a crucial regulator of autophagy. However, the roles and regulatory mechanisms by which MCOLN1 mediates autophagy in lung cancer (LC) remain largely unknown. The expression of MCOLN1 in LC cells and its influence on prognosis were analyzed. The effect of MCOLN1 on cell migration and invasion was analyzed using a scratch test and Transwell assay. The level of autophagy was reflected by evaluating the levels of autophagy marker proteins LC3 and p62 and the changes in autophagy flux. Through gene set enrichment analysis (GSEA), signaling pathways enriched by MCOLN1 were discovered. The levels of endoplasmic reticulum stress (ERS)–related genes and marker proteins were detected to assess the ERS state. An LC xenograft tumor model was constructed to verify the effect of MCOLN1 on tumor growth and autophagy in vivo. MCOLN1 was greatly upregulated in LC cells, which was linked with poor prognosis. Functionally, MCOLN1 boosted LC cells to migrate and invade, which was achieved by inducing autophagy. Further analysis demonstrated that MCOLN1 was enriched in the ERS pathway, and knockdown of MCOLN1 could reduce LC migration and invasion by repressing ERS and blocking cell autophagy, while the addition of the ERS inducer NiCl 2 reversed the effect of MCOLN1 knockdown. Moreover, in vivo experiments confirmed that MCOLN1 can mediate ERS‐induced autophagy to boost LC growth. MCOLN1 plays a carcinogenic role in LC migration and invasion by regulating ERS‐induced autophagy. Repressing the MCOLN1/ERS/autophagy axis is likely to be a potential therapeutic strategy for LC.