Sestrins as a Therapeutic Bridge between ROS and Autophagy in Cancer

Abstract

The regulation of Reactive Oxygen Species (ROS) levels and the contribution therein from networks regulating cell metabolism, such as autophagy and the mTOR-dependent nutrient-sensing pathway, constitute major targets for selective therapeutic intervention against several types of tumors, due to their extensive rewiring in cancer cells as compared to healthy cells. Here, we discuss the sestrin family of proteins—homeostatic transducers of oxidative stress, and drivers of antioxidant and metabolic adaptation—as emerging targets for pharmacological intervention. These adaptive regulators lie at the intersection of those two priority nodes of interest in antitumor intervention—ROS control and the regulation of cell metabolism and autophagy—therefore, they hold the potential not only for the development of completely novel compounds, but also for leveraging on synergistic strategies with current options for tumor therapy and classification/stadiation to achieve personalized medicine.

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…Redox homeostasis is also regulated by non-enzymatic proteins as SESNs or mitochondrial uncoupling proteins (UCPs). SESNs are a family of highly conserved stress-inducible proteins that are strongly up-regulated by oxidative stress as an antioxidant adaptive response [45,46]. During oxidative stress, their expression may be controlled from induced transcription factors, such as p53, Nrf2, or FOXO.…”

“…A recent report demonstrated that SESN2 can inhibit the pro-oxidant enzyme NADPH oxidase 4 (NOX4), preventing pathogenic amounts of cytosolic ROS [48]. SESNs may also contribute to redox homeostasis through the regulation of AMPK-mTORC1 signaling pathways, preventing mammalian target of rapamycin complex 1 (mTORC1) hyperactivation [49] which may enhance ROS production via inhibition of autophagy [50] or directly acting on mitochondrial function [46]. SESN-dependent inhibition of mTORC1 can be also important for autophagy-mediated degradation of Keap1, the inhibitor of Nrf2 [46].…”

“…SESNs may also contribute to redox homeostasis through the regulation of AMPK-mTORC1 signaling pathways, preventing mammalian target of rapamycin complex 1 (mTORC1) hyperactivation [49] which may enhance ROS production via inhibition of autophagy [50] or directly acting on mitochondrial function [46]. SESN-dependent inhibition of mTORC1 can be also important for autophagy-mediated degradation of Keap1, the inhibitor of Nrf2 [46]. UCP proteins, a family of five members in mammals, also has a key role as redox sensor localized in the inner mitochondrial membrane.…”

“…Indeed, AMPK-mediated phosphorylation might modulate the ability of PGC-1α to dock on certain transcription factors or affect the binding or function of other cofactors in the PGC-1α coactivator complex. Therefore, both SESNs and AMPK responses participate in a functional axis that maintains metabolic and redox homeostasis in the cells and its alteration leads increasing oxidative stress and tumor progression [46,83].…”

Mitochondria and Cancer

“…Therefore, such regulation could be a potential target mechanism for cancer treatment. Based on this idea, Sanches-Ávarez et al [4] recognize the sestrin family of proteins as a "missing link" between ROS and autophagy in cancer cells. In their review "Sestrins as a Therapeutic bridge between ROS and Autophagy in Cancer", the authors discuss possibilities for the adaptive regulation of ROS-induced autophagy by sestrins.…”