Mitocurcumin induces ROS-/JNK-mediated paraptosis to overcome chemoresistance in non-small cell lung cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide. A major barrier to effective treatment is the development of drug resistance, which contributes to poor patient survival. One key mechanism underlying this resistance is the ability of cancer cells to evade apoptotic cell death. Thus, there is an urgent need for novel therapeutic strategies to overcome chemoresistance in lung cancer. The ultrastructural features of mitochondria and the endoplasmic reticulum (ER) were assessed using transmission electron microscopy (TEM). Transcriptomic profiling of A549 cells was carried out through whole-exome sequencing. Protein expression levels were validated by western blot analysis, while mitochondrial calcium content was quantified using flow cytometry. Our study utilized mitocurcumin (mitoC) to study an alternative form of cell death in NSCLC. Mitochondria and ER vacuolation and swelling were observed upon mitocurcumin treatment. MitoC treatment upregulated ER and mitochondria stress protein levels in A549 and A549R cells. However, the inhibition of intracellular ROS and JNK pathway abrogated mitoC-induced mitochondria and ER stress proteins. Moreover, we observed that mitoC treatment enhanced mitochondrial calcium uptake in A549 and A549R cells, which gets abrogated upon ROS/JNK signaling inhibition. MitoC exerted organellar stress related to paraptosis in A549 and A549R cells through activation of the ROS-mediated JNK signaling pathway and induced mitochondrial calcium uptake.