Analysis of the metabolic profile and mathematical modeling of cisplatin-induced chemoresistant A549 NSCLC cells through Jardi1b overexpression

• Grant number: 19/08147-7
• Support type: Scholarships abroad - Research
• Effective date (Start): July 01, 2019
• Effective date (End): August 31, 2019
• Field of knowledge: Health Sciences - Medicine
• Principal researcher: Tharcisio Citrangulo Tortelli Junior
• Grantee: Tharcisio Citrangulo Tortelli Junior
• Host: Robert Gillies
• Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Research place: Moffitt Cancer Center, United States
• Associated research grant: 15/26580-9 - Cancer gene therapy: strategic positioning for translational studies, AP.TEM

Abstract

Unlike untransformed cells, tumor cells use the glycolysis as the primary source of energy, even when sufficient oxygen is available for oxidative phosphorylation in the mitochondria (Warburg effect). Recently, tumor subpopulations that are able to utilize mitochondria as the primary energy source have been discovered. These subpopulations are highly resistant to different types chemotherapy and are responsible for tumor repopulation in several models, such as melanoma, breast and prostate cancer. Jardi1b, a histone demethylase, is responsible for changing the metabolic profile of these subpopulations into the oxidative phosphorylation, by overexpressing proteins related to the mitochondrial oxidative phosphorylation and its knock-down or the pharmacological inhibition of the oxidative phosphorylation by biguanides, such as metformin, has been able to increase the sensitization of these Jarid1b-high cells against chemotherapy. In non-small cell lung cancer, metformin sensitizes to cisplatin in a p53-dependent manner, but this chemosensitization is lost if there is previous treatment with a sub-lethal dose of cisplatin. Sub-lethal treatment with cisplatin increases the expression of Jarid1b, which is responsible for the protection of this tumor type against the combined treatment between metformin and cisplatin, through p53 downregulation and through the modulation of cell metabolism. Modeling how these Jarid1b-overexpressing cells are generated in the tumor can be useful to predict the development of resistant cells after cisplatin treatment and, therefore, new treatments that avoid the emergence of resistant cells can be simulated and then tested in vivo.