L Nájera1, M Alonso-Juarranz2, M Garrido3, C Ballestín2, L Moya4, M Martínez-Díaz5, R Carrillo4, A Juarranz6,7, F Rojo2, J M Cuezva3,5,8, J L Rodríguez-Peralto3,9. 1. Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain. 2. IIS-Fundación Jiménez Diaz, C/Reyes Católicos 2, 28049, Madrid, Spain. 3. Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain. 4. Servicio de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Madrid, Spain. 5. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain. 6. Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, C/Darwin, 2, 28049, Madrid, Spain. 7. Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain. 8. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain. 9. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), ISCIII, Madrid, Spain.
Abstract
BACKGROUND: Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. OBJECTIVES: To investigate the role of the mitochondrial proteins, β-subunit of the H+ -ATP synthase (β-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. MATERIALS AND METHODS: The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. RESULTS: The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival. CONCLUSIONS: A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.
BACKGROUND: Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. OBJECTIVES: To investigate the role of the mitochondrial proteins, β-subunit of the H+ -ATP synthase (β-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. MATERIALS AND METHODS: The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. RESULTS: The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanomahuman samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival. CONCLUSIONS: A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation.
Authors: Laura Torresano; Fulvio Santacatterina; Sonia Domínguez-Zorita; Cristina Nuevo-Tapioles; Alfonso Núñez-Salgado; Pau B Esparza-Moltó; Lucía González-Llorente; Inés Romero-Carramiñana; Cristina Núñez de Arenas; Brenda Sánchez-Garrido; Laura Nájera; Clara Salas; Mariano Provencio; José M Cuezva Journal: Oncogenesis Date: 2022-05-09 Impact factor: 6.524
Authors: Marta Mascaraque-Checa; María Gallego-Rentero; Jimena Nicolás-Morala; Mikel Portillo-Esnaola; José M Cuezva; Salvador González; Yolanda Gilaberte; Ángeles Juarranz Journal: Mol Metab Date: 2022-04-09 Impact factor: 8.568