Crosstalk Between Autophagy and Paraptosis: A New Frontier in Cancer Therapy.

Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers.