Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis

GUERON, GERALDINE; ANSELMINO, NICOLÁS; CHIARELLA, PAULA; ORTIZ, EMILIANO G.; LAGE VICKERS, SOFIA; PAEZ, ALEJANDRA V.; GIUDICE, JIMENA; CONTIN, MARIO D.; LEONARDI, DAIANA; JAWORSKI, FELIPE; MANZANO, VERÓNICA; STRAZZA, ARIEL; MONTAGNA, DANIELA R.; LABANCA, ESTEFANIA; COTIGNOLA, JAVIER; D´ACCORSO, NORMA; WOLOSZYNSKA-READ, ANNA; NAVONE, NORA; MEISS, ROBERTO P.; RUGGIERO, RAÚL; VAZQUEZ, ELBA

Cell Death & Disease

SpringerNature

Lugar: Londres; Año: 2017 vol. 9

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that theconcomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROSdamagedphenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible forCR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate,lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostatecancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CRphenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protectiveamino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability,downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyradministration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, andLMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach toboost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.