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

Abstract

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. 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 prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino 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-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.

• Authors: Geraldine Gueron, Nicolás Anselmino, Paula Chiarella, Emiliano G Ortiz, Sofia Lage Vickers, Alejandra V Paez, Jimena Giudice, Mario D Contin, Daiana Leonardi, Felipe Jaworski, Verónica Manzano, Ariel Strazza, Daniela R Montagna, Estefania Labanca, Javier Cotignola, Norma D Accorso, Anna Woloszynska-Read, Nora Navone, Roberto P Meiss, Raúl Ruggiero, Elba Vazquez
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 2 Pg. 140 (02 02 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29396431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Tyrosine
• Phenylalanine
• 3-tyrosine

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Drug Resistance, Neoplasm
• Humans
• Male
• Mice, Nude
• Neoplasm Metastasis (pathology)
• Phenylalanine (metabolism)
• Prostatic Neoplasms (pathology)
• Reactive Oxygen Species (metabolism)
• Serum
• Signal Transduction
• Subcutaneous Tissue (pathology)
• Tyrosine (metabolism)
• Xenograft Model Antitumor Assays