Sestrins as a Therapeutic Bridge between ROS and Autophagy in Cancer.

Bazhin Bazhin,Strippoli Strippoli,Donadelli Donadelli,Cordani Cordani,Sánchez-Álvarez Sánchez-Álvarez

doi:10.3390/cancers11101415

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.

Highlights

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
Intracellular ROS levels are tightly controlled by intricate networks of antioxidant molecules, as the glutathione pair (GSSG/GSH) or the nicotinamide adenine dinucleotide pair (NADH/NAD+ ); and associated redox enzymes, as superoxide dismutases (SODs), catalase, glutathione peroxidases (GPXs), peroxiredoxins (PRXs) or thioredoxins (TRXs)
Some studies revealed that a SESN-dependent and AMPK-independent mechanism for Mechanistic Target Of Rapamycin Complex 1 (mTORC1) extracellular environment, which is a key signal in the regulation of the mTORC1 pathway (Figure 2)

Summary

Regulation of ROS Levels in Physiology

Intracellular ROS levels are tightly controlled by intricate networks of antioxidant molecules, as the glutathione pair (GSSG/GSH) or the nicotinamide adenine dinucleotide pair (NADH/NAD+ ); and associated redox enzymes, as superoxide dismutases (SODs), catalase, glutathione peroxidases (GPXs), peroxiredoxins (PRXs) or thioredoxins (TRXs). These as yet poorly understood networks are integrated with signaling pathways and functional modules that directly impact ROS levels, as is the case of protein folding routes in the endoplasmic reticulum [3], or the superoxide dismutase activities in the mitochondria [4].

A Prominent Example of the Cell Conundrum

Macroautophagy

Dual Role of Autophagy in Cancer

The Sestrin Protein Family

Sestrins as Master Regulators of ROS Management

Sestrins and regulation

Sestrins and the Therapeutical Management of Cancer

Modulation of SESNs by Natural Compounds

Other Therapeutics Acting on SESNs Expression

Conclusions