A group of scientists has unearthed a remarkable ability of the tumor suppressor protein known as Prostate apoptosis response-4 (Par-4) to induce a distinct form of cell death called ferroptosis in human glioblastoma, the most prevalent and aggressive type of brain tumor, without harming normal cells. This newfound insight holds promise for the development of innovative therapies for a variety of challenging-to-treat cancers and neurodegenerative conditions.
Ferroptosis, a process triggered by the iron-mediated generation of reactive oxygen species (ROS) leading to lipid peroxidation, plays a vital role in reducing cancerous tumors. For the first time, it has been revealed that Par-4, previously known for eliminating cancer cells through apoptosis, a programmed cell death mechanism, can also drive ferroptosis in glioblastoma cells.
The tumor suppressor Par-4 is broadly present in different species but tends to be diminished, altered, or deactivated in the context of various cancers. In a study titled “Tumor suppressor Par-4 activates autophagy-dependent ferroptosis,” recently published in the journal Communications Biology, researchers pinpointed Par-4’s unexpected function in promoting ferroptosis-driven cancer regression. They illustrated that Par-4 initiates the activation of ferritinophagy (the autophagic breakdown of ferritin) through the nuclear receptor co-activator 4 (NCOA4). This activation is crucial for the buildup of the labile iron pool, ROS production, and subsequent lipid peroxidation, all culminating in ferroptosis.
Ferroptosis plays a critical role in various health conditions such as cancer, heart disease, brain injury, kidney dysfunction, lung damage, and neurodegenerative disorders like Parkinson’s, Huntington’s, and Alzheimer’s. The recognition of Par-4 as a pivotal player in ferroptosis is paramount as it participates in the fundamental processes and signals driving this alternative cell death route. Numerous cancer cells are unresponsive to current treatments or have developed resistance to existing drug therapies.
This research was a collaborative endeavor between Associate Professor Mazin Magzoub’s laboratory at NYU Abu Dhabi and Professor Vivek M. Rangnekar from the University of Kentucky, the discoverer of Par-4 in 1993.
“The revelation by our team that Par-4 instigates ferroptosis represents a breakthrough in the domain of cancer therapy innovation,” stated Galadari, the Senior Vice Provost for Research and Managing Director of the Research Institute at NYU Abu Dhabi. “The development of approaches to trigger alternative cell death pathways opens up fresh avenues for crafting more potent and efficient therapies for glioblastoma and other lethal and debilitating ailments.”
“Pursuing research at establishments like NYUAD is pivotal in the conversion of the UAE into a knowledge-driven economy that lures local, regional, and global talents — a mutually beneficial relationship that engenders opportunities, knowledge, and prosperity,” Galadari remarked.
