Krebswissenschaft und -therapie

Demethylation with 5-Aza-2²-deoxycytidine Affects Oxidative Metabolism in Human and Mouse Non-small Cell Lung Cancer Cells

Abstract

Agnieszka J Sok, Agnieszka Gizak, Piotr Mamczur, Aleksandra Piotrowska, Agata Knapik, Jerzy Kolodziej, Piotr Dziegiel, Jacek R Wisniewski and Dariusz Rakus

Background: Non-small cell lung cancer is the most common cause of death from cancer in the world. Here we demonstrate the effect of 5-aza-2’-deoxycytidine (5-dAza), which is one of the most promising anticancer drugs, on the growth and metabolism of mouse (KLN205) and human non-small cell lung cancer-derived (hNSCLC) cells.

Results: In both cell lines we observed reduction of the cells viability and rate of their proliferation after 5-dAza treatment. These changes correlated with the lowering of ATP synthesis and lactate release from cells and with overproduction of reactive oxygen species. 5-dAza-treatment of lung cancer cells also induced a decrease of mitochondrial membrane potential and damage of mitochondrial network. These changes were partially reversed by rotenone treatment which also facilitated the cells survival. Proteomic analysis revealed that the demethylation affected the abundance of proteins associated to energy metabolism, especially those of tricarboxylic acid cycle (TCA) and oxidative phosphorylation metabolism (OXPHOS).

Conclusion: Taken together, our work provide evidence that the mechanism of the toxic effect of 5-dAza basically relies on the alteration of mitochondrial function via dysregulation of proteins involved in TCA and OXPHOS.