Home ENGLISH MAGAZINE EneMY Coin: one side enhances energy while the other escapes immunity

EneMY Coin: one side enhances energy while the other escapes immunity

Protein c-Myc is a major 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 lung, breast, pancreatic and cancers and along with leukemias, 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.

The advantage to express c-myc is pivotal for their metabolism. Cancer cells typically display high glucose uptake, glycolytic metabolism, and lactate production even in the presence of oxygen (“aerobic glycolysis”), a phenomenon termed the Warburg effect. This seemingly wasteful use of glucose is most likely due to the higher capacity of glycolysis to produce ATP compared to the oxidative phosphorylation; hence, aerobic glycolysis may satisfy the high demand of rapidly growing cells for ATP. Metabolic labeling using 13C‐glucose reveals that oncogenic levels of c-Myc promote high consumption of glucose. Myc exerts its effects on glucose metabolism by increasing the expression of the glucose transporter GLUT1 and by upregulating the expression of glycolytic enzymes, including hexokinase 2 (HK2), phosphofructokinase‐M1 (PFKM1) and enolase 1 (ENO1). Aerobic glycolysis is also driven by the expression of the M2 isoform of the pyruvate kinase (PKM2), which is virtually expressed in all cancers. However, some evidence suggests that c-Myc might also control the subsequent “translation” of these mRNAs into proteins, a process carried out by ribosomes.

C-Myc enhances expression of PKM2 by promoting the expression of hnRNP splicing factors, as demonstrated in glioma. Scientists now delved into the mechanisms by analyzing 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. Curiously, 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.

Intriguingly, deregulated MYC expression also blocks the induction of mRNAs encoding gluconeogenesis enzymes in response to a high‐fat diet in liver, arguing that repressive functions of MYC contribute to alterations in cellular metabolism. Overexpressing Myc enhances lactate dehydrogenase (LDHA) expression and typically results in extracellular acidification due to the increased production of lactate. Myc also promotes the secretion of lactate through the expression of a monocarboxylate transporter (MCT1). Lactate is not simply a waste product of tumors, but an active role of this metabolite in promoting multiple pro‐oncogenic functions emerged over time. It acidifies cytoplasm like the activation of sodium-proton antiporter NHE-1 triggered by growth factors (e-g- EGF, bFGF, etc.), to induce cellular proliferation. Lactate is secreted by malignant cells to impair the activity of immune system as well. This has, for example, demonstrated in breast cancers especially the triple negative (TNBC). TNBC cells show increased rates of glycolysis and extracellular acidification rate, in comparison to other breast cancer subtypes. Furthermore, TNBC cell lines display more glycolytic dependence compared to luminal breast cancer cell lines; indeed, treatment with the glycolysis inhibitor 2-deoxyglucose markedly reduced their proliferation.

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, latest researchers 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.

Who knows what else will this face-off player show in the future.

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

Scientific references

Wang JX et a. Int J Mol Sci. 2020 Nov; 21(21):8363.

Singh K et al. J Exp Med. 2019 Jul; 216(7):1509-1524.

Spevak CC, Park CY. JNCI 2019 Jan 1; 112(1):7-9.

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

Angelin A et al. Cell Metab 2017; 25(6):1282-1293.

Dott. Gianfrancesco Cormaci
- 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. - Guardia medica presso strutture private dal 2010 - 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). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - 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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