Unveiling m-Tyrosine?s anti-tumoral effect and clinical implications for prostate cancer.

GUERON GERALDINE; ANSELMINO NICOLAS; CHIARELLA PAULA; ORTIZ EMILIANO G.; PAEZ ALEJANDRA V.; SCHUSTER FEDERICO; LEONARDI DAIANA B.; MEISS ROBERTO; RUGGIERO RAUL; NAVONE NORA; VAZQUEZ ELBA S.

Encuentro; 22ND ANNUAL PCF SCIENTIFIC RETREAT; 2015

Prostate Cancer Fundation

Background: The phenomenon, by which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis, is known as concomitant tumor resistance (CR). Clinical and experimental evidence suggest that the removal of human and murine tumors might be followed by an abrupt increase in metastatic growth, hence the primary tumor could exert a controlling action on its metastases. T-cell dependent processes mediate CR in hosts bearing immunogenic murine T-lymphoma (LB) small tumors. However, we have previously showed that a mixture of meta-tyrosine (m-Tyr) and ortho-tyrosine (o-Tyr), two isomers of tyrosine, not present in normal proteins, are the serum anti-tumoral factors responsible for CR induced by immunogenic and non-immunogenic LB large tumors. Here, we investigated whether CR was occurring in human prostate cancer (PCa) experimental models.Methods: Athymic nude mice were inoculated s.c. in the right flank, with the human prostate cancer cell line PC3 (1 x 106, primary implant). After 14 days the animals received a second inoculation of PC3 cells in the left flank (1 x 106, secondary implant). The control group only received the secondary implant. For m-Tyr detection, serum samples were dialized, lioflized and subjected to HPLC. Cell viability and cell cycle distribution, were assessed by MTS and FACS, respectively. RNA and protein expression levels were analysed by RT-qPCR and WB. STAT3 intracellular distribution was analysed by confocal microscopy.Results: m-Tyr was detected in the serum of mice bearing the prostate xenografts. Moreover, the tumor growth inhibition was recapitulated in animals inoculated with the primary tumors and injected with m-Tyr. The RC phenomenon was reversed when secondary implants were injected with phenylalanine (Phe), a protective amino acid highly present in primary tumors. In vitro results also showed that exposure of PC3 cells to m-Tyr inhibited cell growth, induced G0/G1 cell cycle arrest, altered the expression levels of survivin, Ki67 and Hes1; impaired the NFB/STAT3 pathway and induced autophagy; these effects were reversed by Phe treatment. Strikingly, m-Tyr periodic intravenous administration provoked a dramatic reduction of experimental lung metastases generated in mice bearing PC3 human tumors.Conclusions: here we demonstrate for the first time that RC occurs in experimental human solid tumors, effect mediated by m-Tyr, providing insight into the molecular signaling involved in this phenomenon with high potential clinical implications for metastatic PCa.