p53 face-off: from tumor suppressor to growh enhancer?

Search for a description of p53 and it becomes clear that this human protein is widely known for its cancer-fighting benefits, leading to its renown as “the guardian of the genome.” The widely accepted idea is that p53 suppresses cancer, but the new study could argue against that. Scientists at the University of California San Diego have published a new study challenging that description. Studying the “wild type” version of p53 (WTp53), the form that exists broadly in nature, Dr. Jinchul Kim and his colleagues found evidence that in certain cases, WTp53 instead plays a role in promoting tumors, rather than suppressing them. This finding explains an established paradox that, whereas p53 is mutated in more than 50% of all human cancers, it is not frequently mutated in others, such as liver cancer. Now, the scientists describe the culmination of more than four years of research on liver cancer that shows that WTp53 stimulates tumor growth by enhancing cancer metabolism. The key, according to the researchers, is a protein known as PUMA (the acronym for P53 Up-regulated Modulator of Apoptosis), which works inside mitochondria, the cellular power plants.

Along with other tens, PUMA is a p53-induced gene. It belongs to the Bcl-2 family proteins, notoriously involved in apoptosis or programmed cell death. In this family, some members protect from cell death (Bcl-2, Bcl-B, Bcl-XL, Mcl-1, Bcl-W), whilst other have a inducing activity (Bad, Bak, Bid, Bok, Hrk, Noxa, ecc.). PUMA mostly behaves like a killer protein but, according to the experiments, the protein PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier by direct protein interaction. Dr. Xu, a professor in the Division of Biological Sciences’ Section of Molecular Biology, and senior author, explained thoroughly: “Our research found that, at appropriate levels, PUMA disrupts normal function of mitochondria and causes a switch from oxidative phosphorylation, a process for efficient energy production in cells, to glycolysis, an alternative energy path that helps boost cancer metabolism. Indeed, glycolysis is highly preferred in cancer cells and helps them in their proliferative aggressivity. In some cancers it would have the opposite effect by promoting cancer”.

He continue: “That may explain why liver cancer have such a poor prognosis. Our data were based on a mix of data from cell samples, mouse models and human patients. p53 indeed halts the initiation of tumors by reducing the oxidative phosphorylation that produces genome toxins (reactive oxygen species). However, once tumors are established, p53 may function to enhance tumor progression. It’s actually the same function but playing exactly the opposite role in two different contexts. This provides a warning for cancer drug discovery. Drug therapies designed to enhance p53’s function in cancer patients may be inadvertently causing an opposite effect. This role of WTp53 can resolve several long-lasting paradoxes in p53 biology and will be instrumental in the development of cancer therapy, especially in the context of the highly pursued strategies to eliminate human cancer by either activating WTp53 or restoring WTp53 function to p53 mutants in cancers”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Kim J, Yu L et al., Xu Y. Cancer Cell. 2019 Jan 16.

Valente L et al. Oncogene. 2016; 35(29):3866-71. 

Lu J, Tan M, Cai Q. Cancer Lett. 2015; 356:156-64. 

Song H, Xu Y.Cell Cycle. 2007 Jul; 6(13):1570-73.

Informazioni su Dott. Gianfrancesco Cormaci 1365 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it