The oxidized aminoacid m-tyrosine reshapes the metabolic fate of tumors cells impairing metastases

VAZQUEZ ELBA; COTIGNOLA JAVIER; ORTIZ EMILIANO GERMAN; LABANCA, ESTEFANIA; LAGE VICKERS, SOFIA; NAVONE NORA; RUGGIERO, RAUL; GUERON GERALDINE

Mar del Plata

Congreso; LXIII Reunion de la Sociedad Argentina de Investigacion Clinica; 2018

SAIC

Interest in cancer energetics has now become a cornerstone of cancer biology. The accelerated aerobic glycolysis with an increase in lactate production in cancer cells has been first postulated by Warburg. Although aerobic glycolysis is inefficient in terms of energetic resources, the capacity to produce intermediates must be a key driver to rule metabolism in cancer cells. The acquired metabolic signature contributes to the failure of therapy. Previousresults from our laboratory have shown for the first time the phenomenon of concomitant resistance (CR) in human solid tumors, effect mediated by m-Tyrosine (m-Tyr), a potent anti-tumoral oxidized aminoacid exhibiting undetectable toxic-side effects. In this work we explored the capacity of i.v m-Tyr administration to impair metastasis. We used spontaneous (naspharingeal and lung) and experimental (prostate) metastases models. Results show a significant reduction in both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and prostate cancer (PCa) experimental metastases.Further, we explored in parallel the effect of m-Tyr on the energetic balance of prostate cancer cells. Our results performed on PC3 cells demonstrated for the first time that m-Tyr is able to reshape the metabolic fate of PCa cells due to the down-regulation of the LDHA gene (RT-qPCR), which encodes for the lactate dehydrogenase, an enzyme involved in the last step of glycolysis. The shift to a less glycolytic phenotype was evidenced by a decrease in the extracellular acidification rate (ECAR), in oxygen consumption rate (OCR) and in ATP production, reflecting an impairment of mitochondrial function. Same results ] were obtained using the C42B cell line. Altogether, these data support a key role of m-Tyr controlling prostate energetic status, thus ascertaining it as a potential option to boost the therapeutic efficacy of the current treatment for metastasis.