The ROS-KRAS-Nrf2 axis in the control of the redox homeostasis and the intersection with survival-apoptosis pathways: Implications for photodynamic therapy

Publication date: Available online 28 October 2019Source: Journal of Photochemistry and Photobiology B: BiologyAuthor(s): Annalisa Ferino, Valentina Rapozzi, Luigi E. XodoAbstractIn highly proliferating cancer cells oncogenic mutations reprogram the metabolism and increase the production of reactive oxygen species (ROS). Cancer cells prevent ROS accumulation by upregulating antioxidant systems. Here we show that an increase of oxidative stress (ROS and singlet oxygen), generated by photoactivated TMPyP4, results in the upregulation of KRAS and of Nrf2, the major regulator of the redox homeostasis. In agreement with a previous observation, the ectopic expression of KRAS G12D or G12 V is found to stimulate Nrf2. This suggests that ROS, KRAS and Nrf2 establish a molecular axis controlling the redox homeostasis in cancer cells. We found that this axis also modulates the function of the NF-kB/Snail/RKIP circuitry, regulating the survival and apoptosis pathways. Our data show that low ROS levels, obtained when Nrf2 is activated by KRAS, results in the upregulation of prosurvival Snail and simultaneous downregulation of proapoptotic RKIP: an expression pattern favouring cell proliferation. By contrast, high ROS levels, obtained when Nrf2 is inhibited by a small molecule (luteolin), favour apoptosis by upregulating proapoptotic RKIP and downregulating prosurvival Snail. The results of this study are useful to design efficient photodynamic therapy (PDT) against cancer. We hypothesiz...
Source: Journal of Photochemistry and Photobiology B: Biology - Category: Speech-Language Pathology Source Type: research