giovedì, Aprile 18, 2024

Sempre più spazio per la ketamina nel trattamento della depressione resistente: come fa a “resettare” i circuiti?

Background Le stime attuali indicano che oltre 300 milioni di...

Proteasome anchors to neuronal membranes to become a signaling platform: moonlightner or hidden deceiver?

Within the nervous system, the proteasome system (PROS) has...

Intelligenza Artificiale al servizio dell’oncologia (II): adesso è il turno dei tumori cerebrali

Introduzione I tumori al cervello, sebbene rari, rappresentano una sfida...

Lactate: that useless disposable junk, working as a genetic regulator in cancer cells

Described by Otto Warburg a century ago, accelerated glucose consumption and lactate production under fully aerobic conditions is ubiquitous in solid cancers. Observations of accelerated glucose uptake and lactate secretion under fully aerobic conditions led Warburg to posit that cancer could be attributed to an injury to the cellular respiratory system (mitochondria). Still, for many decades lactate was considered a “waste” product resulting from lack of oxygen. However, pioneering work and discoveries by George Brooks since the 1980’s have demonstrated that lactate is the preferred fuel for most cells, the main gluconeogenic precursor in the body, and a signaling molecule (a “lactormone” and “myokine”) capable of inducing gene expression. In concert, Zhang et al. have reported recently, that the key role of lactate in histone acetylation (“lactylation”) is the acetylation of lysine histone residues, acting as an epigenetic modulator and increasing gene transcription.

In 2017, scientists San-Millan and Brooks developed the “lactagenesis hypothesis” by which we posited that accelerated lactate production in tumors was not for bioenergetics, but rather owing to its powerful signaling properties, the role of lactate in tumors was to stimulate carcinogenesis. Posteriorly, in 2019 they demonstrated that lactate functions as an “oncometabolite” and regulates the expression of major genes related to carcinogenesis in MCF7 breast cancer cells. Now, the same team demonstrated that both estrogen-positive (ER+) MCF7 breast cancer cells and triple-negative MDA-MB-231 breast cancer cells (TNBC) use lactate as fuel and driver of gene expression. However the effects have been different, thought an interesting finding is that lactate enhanced the epitelial-mesenchimal transition (EMT), a phenomenon linked to cell immaturity and tissue invasion (metastasis).

Endogenous lactate regulates the expression of multiple genes involved in carcinogenesis. In MCF7 cells, lactate increased the expression of growth factors (EGFR, VEGF) and mitogenic signaling components (KRAS, mTOR, PIK3CA, TP53 and CDK4); while decreased the expression of regulators of DNA repair and genomic stability (ATM, BRCA1, BRCA2, E2F1, MYC) mainly at 48h of exposure. On the other hand, in the MDA-MB-231 cell line, lactate slightly changed the composition, enhancing ATM and E2F1 (repressed in MCF7 cells), while repressing CDK4 and CDK6 cell cyle kinases (enhanced in MCF7 cells). Finally, lactate decreased E-cadherin protein expression in MCF7 cells and increased vimentin expression in MDA-MB-231 cells. Both these proteins are involved in cell motility and, in general, MCF7 cells are characterized by an epithelial phenotype, while MDA-MB-231 a mesenchymal one.

This could explain the effect of lactate on the phenotype of thiese cancer cells. TNBC cells possess significantly higher amount of vimentin than ER+ cancer cells, which could explain their higher eggressivity compared to the latter. Importantly, we found that lactate elicits overexpression of a key tumor suppressor gene, TP53 in both cancer cell lines. Although P53 is typically considered a “tumor suppressor” protein that binds to and repairs damaged DNA or signals for apoptosis in irreparable cells, missense mutations in TP53 elicit mutant p53 proteins with potential gain-of-function properties that stimulate tumor cell proliferation, migration, invasion, survival, chemoresistance, cancer metabolism, and/or tissue architecture disruption. Consequently, overexpression of P53 may be associated with increased mortality and poor prognosis, especially for the triple negative breast cancer, though ER+ tumors may sometime be aggressive as well.

In conclusion, lactate is just not a “waste” or “junk disposable” molecule that cancer cells produce from their metabolism. Considered its more and more important “gamekeeping” role, scientists deem that blocking cellular lactate production as well as the exchange between cancer cells and surrounding stroma cells, affecting the tumor microenvironment, should be a priority in cancer research.

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

Scientific references

San-Millan I et al. bioRxiv 2023 Mar 23: 533060.

Jiang J et al. Frontiers Oncol 2021; 11: 647559.

Di Zhang ZT et al. Nature 2019; (574): 575-580.

Mishra D, Banerjee D. Cancers (Basel) 2019; 11(6).

San-Millan I, Brooks GA. Carcinogenesis 2017; 38(2):119.

Latest

Newsletter

Don't miss

Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

Perdere peso in età avanzata? Si, con più proteine ma senza perdere le ossa

I geriatri hanno dibattuto a lungo su come raccomandare una sicura e salutare perdita di peso agli adulti o agli anziani in sovrappeso, poiché...

La salute e la malattia muscolare nel diabete: i meccanismi, le possibilità, le sfide

Background  Il diabete è un crescente problema di salute e sanità pubblica, che continua ad aumentare nonostante gli sforzi della ricerca e dell’assistenza sanitaria. A...

Comparsa di disturbi mentali nei problemi riproduttivi: indagine estesa su cosa si cela sotto

Introduzione I disturbi associati al benessere mentale femminile e al tratto riproduttivo comunemente coesistono; tuttavia, la causa precisa della co-occorrenza non è chiara. Le cause...