RESUMO
Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma de Células Escamosas/genética , Metabolismo Energético/genética , Neoplasias de Cabeça e Pescoço/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Movimento Celular/genética , Proliferação de Células , Ativação Enzimática/genética , Fluoruracila/farmacologia , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Transplante de Neoplasias , Ligação Proteica/genética , Interferência de RNA , RNA Interferente Pequeno , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais/genética , Esferoides Celulares/citologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
High doses of ß-phenylethyl isothiocyanate (PEITC), a phytochemical in cruciferous vegetables, are not feasible for consumption due to a strong mouth-tingling effect. This study investigated the anti-cancer effect of PEITC at sensory acceptable doses. In vitro, PEITC was selectively toxic to oral cancer cells (CAL-27, FaDu, SCC4, SCC 9, SCC15, SCC25 and TU138), compared to oral keratinocytes (OKF6/TERT2 and NOK/Si). In vivo, 5 and 10 mg kg-1 PEITC, equivalent to human organoleptically acceptable doses, retarded tumor growth and prolonged the survival of mice bearing p53-mutated oral cancer cells - TU138 xenograft. Mechanistically, PEITC induced ROS accumulation, nuclear translocation of p53 and p21 and G1/S cell cycle arrest in vitro; increased p53 and 8-oxo-dG levels; and decreased Ki-67 intense/mild staining ratios without TUNEL changes in vivo. These findings suggested that the sensory acceptable doses of PEITC selectively induced ROS-mediated cell cycle arrest leading to delayed tumor progression and extended survival. PEITC could be a functional ingredient for oral cancer prevention.