Face-off oncogene: one side enhances energy, the other escapes immunity

A group of researchers led by Dr. Hans-Guido Wendel at Memorial Sloan Kettering Cancer Center, Dr. Zhengqing Ouyang at The Jackson Laboratory for Genomic Medicine and Dr. Gunnar Rätsch at the ETH Zürich, have discovered surprising new functions for a protein called c-Myc, a powerful oncogene that is estimated to drive the development of almost 500.000 new cancer cases in the US every year. This oncogene enhance the aggressivity of tumors like leukemias, lung, breast, pancreatic cancers and colo-rectal carcinoma, to mention some. The main mechanism of its oncogenic action is its enhanced synthesis, though activating mutations of his gene have been discovered. Originally this oncogene, along with its viral counterpart, v-myc, was studied for its ability to transform bone marrow cells and enhance the onset of leukemia. Though has been discovered more than 30 years ago and deeply studied, new data shows that c-Myc still has hidden tricks up to its sleeve. Beside proliferation, it may indeed affect the quality of protein production in lymphoma cells, altering their susceptibility to immunotherapy. C-Myc drives the development of a wide range of cancers by enhancing the growth and proliferation of tumor cells. This is mainly due to its role as a transcription factor controlling the production of messenger RNAs (mRNAs) from thousands of different genes within the cell.

However, some evidence suggests that c-Myc might also control the subsequent “translation” of these mRNAs into proteins, a process carried out by cellular organelles known as ribosomes. The team analyzed the types of mRNA translated by ribosomes in lymphoma cells containing either low or high levels of c-Myc. The researchers determined that high levels of this factor stimulate the translation of a specific set of mRNAs, many of which encode proteins of the respiratory complexes that allow the cell’s mitochondria to produce energy. The research team found that, in the absence of c-Myc, the proteins SRSF1 and RBM42 can bind to these mRNAs and prevent them from being translated by ribosomes. When c-Myc levels are high, however, SRSF1 and RBM42 no longer bind to the mRNAs, and they are free to be translated into respiratory complex proteins. It will therefore promotes the generation of energy that can fuel the rapid growth and proliferation of lymphoma cells. Far from not being foreseen, but researchers mostly focused their attention on the ability of c-Myc to regulate gene expression of enzymes involved in glycolysis. This chain process lies upstream to mitochondria and is basically the sequence of chemical reactions to burn glucose, the main cellular fuel.

The researchers also discovered that MYC affects how much of an mRNA that ribosomes translate, resulting in the production of longer or shorter versions of proteins. For example, lymphoma cells containing low levels of MYC produce a truncated version of the protein CD19 that, unlike full-length CD19, is no longer exposed on the surface of the cancer cell. This is important because lymphoma can be treated using CAR-T immune cells that have been genetically engineered to recognize and kill CD19-expressing cancer cells. Loss of surface CD19 is associated with resistance to CAR-T cell therapy, but how lymphoma cells reduce surface CD19 levels is still unclear. The researchers found that CAR-T cells were less able to recognize and kill lymphoma cells that lacked surface CD19 because they expressed low levels of c-Myc. Altogether, the study reveals that c-Myc can affect the production of key metabolic enzymes and immune receptors in lymphoma cells by regulating the efficiency of mRNA translation and the integrity of protein synthesis. The researchers now plan to investigate how c-Myc regulates these different aspects of protein synthesis in cancer cells. The study has been published this May 29 in the Journal of Experimental Medicine.

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

Scientific references

Singh K et al., Wendel HG. J Exp Med. 2019 May 29.

Spevak CC, Park CY. J Natl Cancer Inst. 2019 May 22.

Nguyen L et al. Genes (Basel). 2017 Apr 5; 8(4).

Informazioni su Dott. Gianfrancesco Cormaci 1516 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

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