# Sestrins in Carcinogenesis—The Firefighters That Sometimes Stoke the Fire

## TL;DR

Sestrins are stress proteins that can both prevent and promote cancer, depending on the context, and may serve as potential diagnostic and therapeutic tools.

## Contribution

This review clarifies the dual roles of Sestrins in cancer and evaluates their potential as diagnostic and therapeutic targets.

## Key findings

- Sestrin downregulation is commonly observed in cancers and linked to poor prognosis.
- Sestrins inhibit mTORC1 and reduce oxidative stress, which can suppress tumor growth.
- In some contexts, Sestrins promote tumor survival via pathways like AKT signaling.

## Abstract

Sestrins (SESN1-3) are a family of stress-responsive proteins that serve as direct targets of several transcription factors, including tumour suppressor protein p53. Structural studies have identified three core molecular functions of Sestrins: scavenging of reactive oxygen species (ROS), inhibition of mTORC1 signalling, and leucine binding. As leucine-dependent mTORC1 inhibitors and antioxidants, Sestrins regulate metabolism and redox balance, both of which are frequently dysregulated in cancer. Dysregulation of Sestrin expression, most commonly downregulation, is widely observed in cancers and is often associated with increased tumour growth and poor prognosis. However, in certain contexts, Sestrin overexpression may promote tumour survival, and this review explores the molecular mechanisms underlying these seemingly contradictory effects on carcinogenesis, evaluates the evidence for Sestrin involvement across various cancer types, and discusses the potential of Sestrins as diagnostic markers and therapeutic targets.

Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets.