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CHARACTERIZATION OF BIOENERGETIC PHENOTYPE AS HALLMARK OF NON-MUSCLE INVASIVE BLADDER CANCER: BIOENERGETIC SIGNATURE OF LOW-GRADE PTA, HIGH-GRADE PTA AND PT1
Background: To evaluate and understand how the neoplastic cells of each histological grade of the non-muscle-invasive bladder cancer (NMIBC) can undertake strategies of metabolic adaptation to attend the marked demands of cell growth and proliferation seems to be a field with promising perspectives in the best understanding of the behavior of these cells. Therefore, the present study characterized and compared the profile of cellular energetic metabolism in the different histological grades of NMIBC (low-grade pTa, high-grade pTa, pT1), besides allowing the adaptation of the bioenergetic cellular index to these tumors.
Methods: Thirty formalin-fixed paraffin-embedded samples of bladder were collected from patients with NMIBC who underwent transurethral resection and were divided into 3 groups (n= 10 samples per group): low-grade pTa group; high-grade pTa group and pT1 group. These samples were submitted to immunohistochemistry and Western Blotting analyzes: glycolytic pathway markers [Glucose transporter-1 (GLUT-1), Phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and Lactate dehydrogenase A (LDH-A)] and; oxidative phosphorylation (OXPHOS) pathway [Pyruvate Dehydrogenase (PDH), Citrate synthase (CS), Short chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC), Mitochondrial ATP synthase F1-beta-subunit (β-F1-ATP synthase) and heat shock protein 60 (HSP60)]. The bioenergetic cellular (BEC) index were calculated using β-F1-ATPase/HSP 60/GAPDH ratio.
Results: Low-grade NMIBC (low-grade pTa group) showed significant difference (p<0.01) in energy metabolism in relation to high-grade NMIBC (high-grade pTa and pT1 groups). Low-grade tumors showed an avidity for the OXPHOS pathway, while the high-grade tumors by the glycolytic pathway. The low-grade pTa tumors had a high BEC index (p<0.01) because of the predominance of OXPHOS observed by intense immunoreactivity and higher-protein levels of β-F1-ATP synthase and, weak immunoreactivity and low-protein levels of GAPDH. Also, these tumors showed intense immunoreactivity and high-protein levels for HADHSC and PDH and, weak immunoreactivity and low-protein levels for GLUT-1 and PFK.
Conclusions: The association between NMIBC and energetic cellular metabolism is of relevance in establishing clinical-pathological and prognostic criteria as well as helping to develop new therapies focused on the metabolism of these tumor cells that are more effective and with less side effects.
Bladder cancer, Energy metabolism, Bioenergetic signature, Cancer metabolism
Câncer de bexiga
Universidade Estadual de Campinas - São Paulo - Brasil
GUILHERME PRADO COSTA, PETRA KARLA BÖCKELMANN, RENATO PRADO COSTA, CARLOS HERMANN SCHAAL, JOÃO CARLOS CARDOSO ALONSO, LEANDRO LUIZ LOPES FREITAS, OTÁVIO MARTUCCI, ATHANASE BILLIS, WAGNER JOSÉ FÁVARO