Therapy-induced senescence through the redox lens

Abstract

Therapy-induced senescent tumor cells have emerged as significant drivers of tumor recurrence and disease relapse. Interestingly, reactive oxygen species (ROS) production and its associated redox signaling networks are intertwined with initiation and establishment of therapy-induced senescence. Therapy-induced senescent cells influence neighboring cells and the tumor microenvironment via their bioactive secretome known as the senescence-associated secretory phenotype (SASP). The intracellular effects of ROS are dose and context-dependent. Under normal physiological conditions, ROS is involved in various signalling pathways and cellular processes important for maintenance of cellular homeostasis, such as redox balance, stress response, inflammatory signalling, cell proliferation and cell death among others. However excess ROS accompanied by a pro-oxidant microenvironment can engender oxidative DNA damage, triggering cellular senescence. In this review, we discuss the role of ROS and the redox state dynamics in fine-tuning homeostatic processes that drive therapy-induced cell fate towards senescence establishment, as well as their influence in stimulating inflammatory signalling and SASP production. We also offer insights into interventional strategies, specifically senotherapeutics, that could potentially leverage on modulation of redox and antioxidant pathways. Lastly, we evaluate possible implications of redox rewiring during escape from therapy-induced senescence, an emerging area of research. We envision that examining therapy-induced senescence through the redox lens, integrated with time-resolved single-cell RNA sequencing combined with spatiotemporal multi-omics, could further enhance our understanding of its functional heterogeneity. This could aid identification of targetable signalling nodes to reduce disease relapse, as well as inform strategies for development of broad-spectrum senotherapeutics. Overall, our review aims to delineate redox-driven mechanisms which contribute to the biology of therapy-induced senescence and beyond, while highlighting implications for tumor initiation and recurrence.

Keywords: Oxidative stress; ROS; Redox; SASP; Senescence; Therapy.

Fig. 1

ROS as a “molecular toolkit” that fine-tunes molecular and physiological processes for adaptation and malignancy. Basal (low) ROS levels: In normal physiological environments, ROS/redox signalling acts as a physiological rheostat to regulate critical cellular functions for development and adaptation to the surrounding millieu. This maintenance of redox homeostasis is essential to normal cellular activity. High ROS levels: During cancer initiation, intrinsic factors such as oncogenic lesions, and external factors such as the chronic inflammatory environment, shift redox homeostasis into a ‘pro-oxidant’ state. This ‘pro-oxidant’ state in turn facilitates pro-tumorigenic behaviors and selects for higher tolerance against oxidative stress. In this way, alterations in ROS and redox signalling allow fine-tuned adjustments that underlie both physiological and pathological conditions.

Fig. 2

Therapy-induced senescence through the redox lens. (A) Cancer therapy induces high ROS levels and high oxidative stress in cells, causing the formation of telomeric 8-oxoguanine and telomeric oxidative damage. The telomeric lesion is sensed by DNA damage-sensing proteins, causing activation of p53/p21 pathways, resulting in senescence. (B) Genotoxic chemotherapy causes inhibition of DNA replication and the cell cycle, which induces global DNA damage. Double-stranded and single-stranded breaks are sensed by ATM and ATR respectively, inducing a p53 response that results in activation of the senescence program. The p53/p21 response may in turn induce production of ROS via mitochondrial dysfunction, causing increased oxidative DNA damage and persistent DNA damage response signaling. (C) SASP induces paracrine DNA damage as well as increased ROS production via upregulation of NADPH oxidase (NOX). In the absence of genotoxic drugs, ROS-induced DNA damage may play a more prominent role in driving p53 activation, resulting in paracrine senescence. (D) Senescent cells may accumulate at the invasive front of cancers and create high ROS levels, high oxidative stress, and a pro-inflammatory environment via the SASP. Pro-Inflammatory SASP factors then facilitate aggressive and invasive behavior, while the high ROS microenvironment creates an immunosuppresive, tumorigenic-permissive millieu. (E) A small subpopulation of therapy-induced senescent cells may re-enter the cell cycle via upregulation of Cdk1. These “senescence-escaped” cells are phenotypically different to their non-senescent counterparts prior to escape, and are characterized by high self-renewal capacity via upregulation of stemness-related genes. Upon escape from senescence, these cells possess a low ROS, high antioxidant phenotype, in contrast to the senescence-associated pro-oxidant environment. This suggests a redox-rewiring event associated with senescence escape with implications for tumor recurrence.