CONICET | Buscador de Institutos y Recursos Humanos

An imbalance in the antioxidant response, endoplasmic reticulum (ER) homeostasis, and unfolded protein response (UPR) has been associated with several pathologies. Under physiological conditions, different cell types have different levels of UPR components, due in part to their metabolic and protein biosynthetic activity. Placental and tumor cells share many properties such as a high demand for protein synthesis and adaptation to a changing oxygen microenvironment. Krüppel like factor 6 (KLF6) is a transcription factor early activated by hypoxia and other stressors, and although its role as a tumor suppressor has been well established, its function largely depends on the cellular context. Herein, we analyzed KLF6 contribution in redox and ER homeostasis in the non-tumoral trophoblast-derived cell line HTR8/SVneo as well as in T98G, HepG2 and MDA-MB 231 tumoral cell lines. Downregulation of KLF6 by siRNA generated an increase in reactive oxygen species (ROS) in all the cell types analyzed, detected by flow cytometry through the H2DCFDA probe. The expression level of BiP, Ero1α, PDI, calnexin and calreticulin chaperones as well as the activity of Ire1α and PERK pathways, involved in ER homeostasis, were evaluated in KLF6-silenced cells. Results revealed that these UPR components were differentially modulated by KLF6 in each cell line. In addition, components involved in redox balance were analyzed in HTR-8/SVneo cells. At this regard, KLF6 silencing did not modify the canonical ROS-activated Nrf2 pathway as measured by its cytoplasm to nucleus translocation and HO-1 expression. Neither the peroxiredoxins nor the catalase protein levels and its activity were altered. Moreover, the mitochondrial membrane potential determined by flow cytometry through JC-1 dye was not affected. Our results suggest that KLF6 is involved in redox and ER homeostasis modulating UPR components in a cell type dependent-manner.