- 1) Dubbed the 'guardian of the genome', p53 is a tumor suppressor protein that prevents cancer initiation and progression.
2) p53 is mutated and no longer functional in over half of all human cancers. This makes p53 the most mutated protein in cancer, and therefore a key target for cancer therapy.
3) Many of these cancer-associated mutations in p53 cause it to aggregate or clump together into inactive clusters in cancer cells.
4) Using protein mimetics (small molecules that mimic proteins) originally designed to prevent aggregation of proteins associated with Alzheimer's disease and type II diabetes, the researchers were able to breakdown p53 aggregates and reactivate the protein, leading to the death of cancer cells.
Abu Dhabi, UAE: A new study by an international team of researchers, led by NYU Abu Dhabi Associate Professor of Biology Mazin Magzoub, provides important insights into the p53 protein, a critical tumor suppressor often mutated and deactivated in cancer, and a key target in the development of cancer therapeutics.
The Magzoub Lab at NYUAD, in collaboration with Professor and NYU President Andrew Hamilton's lab at NYU New York and Assistant Professor Sunil Kumar's lab at the University of Denver, previously reported the use of small molecule protein mimetics to effectively prevent aggregation of proteins associated with Alzheimer's disease and type II diabetes. In this new study, the team has extended their protein mimetic-based approach and specifically applied it to cancer-associated aggregation of mutant or altered forms of p53.
In the paper titled Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function, published in the journal Nature Communications, researchers in the Magzoub Lab – including Research Associate Loganathan Palanikumar, NYU Abu Dhabi students Laura Karpauskaite and Sarah Hassan, and Instructor of Biology Ibrahim Chehade – and their collaborators at the Hamilton and Kumar labs, along with colleagues at NYU Abu Dhabi – including Research Assistant Professor Mohamed Al-Sayegh, Visiting Professor of Chemistry Gennaro Esposito, and Lecturer of Biology Ahmad J. Afzal – present the process of using protein mimetics to reactivate p53.
The team first screened a library of protein mimetics originally designed to target Alzheimer's disease and type II diabetes. The screen identified a protein mimetic that potently dissociates mutant p53 aggregates and prevents further aggregation of the protein. The researchers then demonstrated that dissociation of mutant p53 aggregates by the protein mimetic restores p53's tumor suppressor function, leading to the death of a wide range of cancer cells. Importantly, treatment with the protein mimetic effectively shrinks tumors that harbor mutant p53, while exhibiting no noticeable toxicity to healthy tissue, thereby substantially prolonging survival.
"With the increasing incidence of cancer worldwide, there is a pressing need for new cancer treatments to supplement or supplant the current ones," said Magzoub. "Here, we have demonstrated the first successful application of a bona fide small-molecule amyloid inhibitor as an anticancer agent. We believe this work will have a broad impact as it effectively establishes a bridge between amyloid diseases and cancer, providing a foundation for cross-informational approaches in the design of new and potent mutant p53-targeted cancer therapeutics."
About NYU Abu Dhabi
NYU Abu Dhabi is the first comprehensive liberal arts and research campus in the Middle East to be operated abroad by a major American research university. NYU Abu Dhabi has integrated a highly selective undergraduate curriculum across the disciplines with a world center for advanced research and scholarship. The university enables its students in the sciences, engineering, social sciences, humanities, and arts to succeed in an increasingly interdependent world and advance cooperation and progress on humanity's shared challenges. NYU Abu Dhabi's high-achieving students have come from over 115 countries and speak over 115 languages. Together, NYU's campuses in New York, Abu Dhabi, and Shanghai form the backbone of a unique global university, giving faculty and students opportunities to experience varied learning environments and immersion in other cultures at one or more of the numerous study-abroad sites NYU maintains on six continents.