There are different forms of cell death occurring in the body: autophagy, apoptosis, necrosis, etc. One such mechanism of cell death is known as ferroptosis.
As the name suggests, ferroptosis is an iron-mediated process of cell death. Ferroptosis is a process in which iron accumulates inside the cell which degrades lipids inside the cell via the process of peroxidation. These lethal lipid products will ultimately lead to cell death.
The Discovery
A team of researchers at NYU 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 – while sparing healthy cells. This new understanding has the potential to inform the development of novel treatments for various hard-to-treat cancers and neurodegenerative diseases.
Prostate apoptosis response-4 (Par-4) was first discovered in 1993 by Professor Vivek M. Rangnekar from the University of Kentucky. There are many pathways that Par-4 exerts for its pro-apoptotic function. It can interact with and inhibit pro-survival pathways, such as the NF-κB pathway, which is often activated in cancer cells to promote their growth and survival. Additionally, Par-4 can bind to the cell membrane receptor GRP78, triggering a cascade of events that lead to apoptosis. Par-4 also has an anti-oxidant mechanism, thereby promoting the production of reactive oxygen species (ROS) and causing cell death.
However, the most intriguing pathway of cell death by Par-4 is ferroptosis. “Our team’s discovery that Par-4 triggers ferroptosis is a breakthrough in the field of cancer treatment development,” said Galadari, who is the Senior Vice Provost for Research and Managing Director of the Research Institute at NYU Abu Dhabi. “Developing methods to activate alternative cell death pathways presents new opportunities for the creation of more potent and effective therapies for glioblastoma and other deadly and debilitating diseases.”
Mechanism of Ferroptosis
The tumor suppressor protein Par-4 is widely expressed across species but is often reduced, mutated, or inactivated in the presence of various cancers. In the study “Tumor suppressor Par-4 activates autophagy-dependent ferroptosis,” recently published in the journal Communications Biology, the researchers identified that Par-4 plays an unanticipated role in promoting ferroptosis-mediated cancer regression.
Par-4 triggers the activation of a process called ferritinophagy. Ferritin is the storage form of iron present in our body. Hence, ferritinophagy is the process of autophagic destruction of ferritin which happens via activation of nuclear receptor co-activator 4 (NCOA4). This leads to the release of labile iron pool inside cells which then leads to the toxic accumulation of reactive oxygen species (ROS). These ROS molecules start damaging cell membranes and lipid molecules via the process of peroxidation. Ultimately, this leads to cell death. This entire process is called ferroptosis.
Ferroptosis plays a key role in various health issues, such as cancer, heart disease, brain damage, kidney failure, lung injury, and diseases like Parkinson’s, Huntington’s, and Alzheimer’s. The identification of Par-4 as a key player in ferroptosis is essential, as it is involved in the main processes and signals that make this alternative cell death pathway, ferroptosis, occur. Many types of cancer cells don’t respond to today’s treatments or have developed resistance to existing drug therapies.
Implications for Ferroptosis
The ability of Par-4 to induce ferroptosis presents several therapeutic advantages:
- Selective Cancer Cell Death: Par-4 has more affinity for cancer cells than normal cells. This leads to a lesser number of side effects which are typically associated with other conventional therapies.
- Overcoming Resistance: Tumors resistant to apoptosis-inducing drugs may still be susceptible to ferroptosis. Par-4 induced ferroptosis offers a potential solution for treating resistant cancers.
- Combination Therapies: Enhancing Par-4 expression or function could be combined with other treatments to maximize therapeutic efficacy. For instance, drugs that inhibit antioxidant defenses or increase iron levels could synergize with Par-4 to induce ferroptosis more effectively.
Challenges and Future Directions
While the potential of Par-4-induced ferroptosis is promising, several challenges remain:
- Delivery Mechanisms: Efficient delivery systems are needed to ensure that Par-4 reaches the tumor site in sufficient quantities.
- Understanding Specificity: More research is required to fully understand why Par-4 selectively induces ferroptosis in cancer cells and not in normal cells.
- Response with other Therapies: The usage of antioxidants or iron chelators along with Par-4 can significantly reduce the efficiency of Par-4 therapy. Anti-oxidants can hamper the production of reactive oxygen species (ROS). Iron chelators reduce the quantities of iron present in blood and thereby reducing the efficacy of ferroptosis.
- Clinical Trials: Rigorous clinical testing is necessary to determine the safety and efficacy of Par-4-based therapies in humans.
Source: NYU Abu Dhabi
Journal reference:
Subburayan, K., Thayyullathil, F., Pallichankandy, S. et al. Tumor suppressor Par-4 activates autophagy-dependent ferroptosis. Commun Biol 7, 732 (2024). https://doi.org/10.1038/s42003-024-06430-z
