A team of researchers at New York University Abu Dhabi, led by Professor Sehamuddin Galadari, has discovered that the tumor suppressor protein Prostate apoptosis response-4 (Par-4) can cause a unique type of cell death called ferroptosis in human glioblastoma (the most common and aggressive type of brain tumor) without affecting healthy cells. This new knowledge has the potential to inform the development of new treatments for several difficult-to-treat cancers and neurodegenerative diseases.
Ferroptosis is triggered by iron-mediated production of reactive oxygen species (ROS) and subsequent lipid peroxidation, which plays a crucial role in shrinking cancer tumors. This is the first time that Par-4, already known to kill cancer cells through apoptosis (a form of programmed cell death), has been shown to promote ferroptosis in glioblastoma cells.
The tumor suppressor protein Par-4 is widely expressed across species, but is often reduced, mutated, or inactivated in the presence of various types of cancer. In the study “Par-4 tumor suppressor activates autophagy-dependent ferroptosis,” recently published in the journal Biology of communicationsThe researchers identified that Par-4 plays an unanticipated role in promoting ferroptosis-mediated cancer regression. They showed that Par-4 triggers the activation of ferritinophagy (autophagic degradation of ferritin) through nuclear receptor coactivator 4 (NCOA4). This activation is required for the accumulation of the labile iron pool, ROS production, and subsequent lipid peroxidation, all of which lead to ferroptosis.
Ferroptosis plays a key role in a variety of health problems, including cancer, heart disease, brain damage, kidney failure, lung injury, and diseases such as Parkinson’s, Huntington’s, and Alzheimer’s. The identification of Par-4 as a key player in ferroptosis is critical, as it is involved in the key processes and signals that trigger this alternative cell death pathway, ferroptosis. Many types of cancer cells do not respond to current treatments or have developed resistance to existing drug therapies.
This research was a collaborative effort between the laboratory of Associate Professor Mazin Magzoub at New York University in Abu Dhabi and Professor Vivek M. Rangnekar of the University of Kentucky, who discovered Par-4 in 1993.
“Our team’s discovery that Par-4 triggers ferroptosis is a major breakthrough in the field of cancer treatment development,” said Galadari, senior vice chancellor for research and general manager of the NYU Abu Dhabi Research Institute. “Developing methods to activate alternative cell death pathways presents new opportunities for creating more potent and effective therapies for glioblastoma and other deadly and debilitating diseases.”
“Investing in research at institutions like NYUAD is critical to transforming the UAE into a knowledge-based economy that attracts local, regional and global talent – a symbiotic relationship that creates opportunity, knowledge and wealth,” Galadari added.