Interplay between ROS and Autophagy in Cancer and Aging: From Molecular Mechanisms to Novel Therapeutic Approaches

Aging and cancer are highly related biological phenomena. Cellular processes that underpin several malignant phenotypic traits, including DNA damage responses, oxidative stress, metabolic rewiring, and cellular senescence, also contribute to aging. Reactive oxygen species (ROS) play an essential role as intra- and extracellular messengers, orchestrating functional and metabolic states of the cell through the regulation of different signaling pathways [1, 2]. Importantly, ROS levels are persistently elevated in cancer cells as a result of their increased metabolic activity, mitochondrial dysfunction, and activation of oncogenes [3]. However, ROS are also powerful oxidizing agents, which can induce cell injury upon modification of lipids, proteins, or DNA, altering normal cell physiology and increasing the risk of DNA mutation and tumorigenesis. Autophagy is a key node for the regulation of ROS levels as well as for ROS-dependent cellular regulation. Autophagy comprises salvaging processes, commonly triggered by metabolic stress responses by which macromolecules and organelles are targeted by autophagic vesicles to lysosomes for degradation and recycling of their constituents [4]. Many studies revealed that alterations in ROS and autophagy are implicated in cancer biology and aging. However, while it is established that high levels of ROS and impaired autophagy drive aging in mammalian cells, their role in regulating cancer cell death or survival is highly contextual and dependent on the source of stress, tumor particularities, and its metabolic status [5]. Despite the fact that both ROS and autophagy can promote tumorigenesis and tumor progression, their exacerbation may induce cell death following a nonspecific injury or an excessive degradation of macromolecules and cellular organelles required for cellular processes. Interestingly, many oncogenic stimuli that induce ROS generation also trigger autophagy, including nutrient starvation, mitochondrial dysfunction, and hypoxia, suggesting the existence of the interplay between ROS and autophagy. Among the plethora of signaling pathways regulating this interplay, the mechanistic Target Of Rapamycin Complex 1 (mTORC1) and 5AMP-activated protein kinase (AMPK) interpret multiple cues, including oxidative stress, to integrate them with the control of energy management, anabolism, and cell growth [6]. Conversely, these signaling systems regulate metabolism and growth which are in turn the major ROS sources themselves. Thus, the understanding of the molecular mechanisms linking ROS and autophagy may acquire an exceptional significance to develop novel, tailored, preventive, and therapeutic strategies against cancer disease and aging processes.