Resveratrol regulates <i>PINK1/Parkin</i>-mediated mitophagy via the lncRNA <i>ZFAS1-miR-150-5p-PINK1</i> axis, and enhances the antitumor activity of paclitaxel against non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) is a common malignant subtype of lung cancer with high mortality. Resveratrol (RSV) is a natural molecule that regulates mitochondrial metabolism. Here, we explored the effect of RSV on NSCLC cell mitophagy and paclitaxel (PTX) resistance. LncRNA ZFAS1, miR-150-5p, and PTEN-induced putative kinase 1 (PINK1) expressions in NSCLC cells were analyzed by RT-qPCR. Levels of PINK1, Parkin and autophagy related molecules LC3I and LC3II were assessed by western blot. Mitophagy was demonstrated by transmission electron microscopy. Luciferase reporter assay revealed that miR-150-5p directly interacted with ZFAS1 or PINK1. MTT was performed to test the IC50 of NSCLC cells. Cell proliferation and apoptosis were measured with CCK-8, EdU, and TUNEL assays. A549/PTX cells exhibited a higher mitophagy activity, and chemoresistance, whereas RSV suppressed PTX resistance and mitophagy in NSCLC cells. Furthermore, ZFAS1 was found to be a downstream effector of RSV in NSCLC cells. We next found ZFAS1 directly interacted with miR-150-5p and regulated the expression of a key mitophagy regulator PINK1. In addition, RSV modulated PTX resistance and mitophagy in NSCLC via ZFAS1/miR-150-5p/PINK1 axis. We validate that RSV influences mitophagy and PTX resistance in NSCLC via ZFAS1/miR-150-5p mediated PINK1/Parkin pathway. Combining these 2 drugs may be a new option of NSCLC therapy.