Abstract
As an intermediate metabolite of the tricarboxylic acid cycle in mitochondria, succinate is widely investigated for its role in metabolism. In recent years, an increasing number of studies have concentrated on the unanticipated role of succinate outside metabolism, acting as, for instance, an inflammatory signal or a carcinogenic initiator. Actually, succinate dehydrogenase gene mutations and abnormal succinate accumulation have been observed in a battery of hereditary and sporadic malignancies. In this review, we discuss the unexpected role of succinate and possible mechanisms that may contribute to its accumulation. Additionally, we describe how the high concentration of succinate in the tumor microenvironment acts as an active participant in tumorigenesis, rather than a passive bystander or innocent victim. Focusing on mechanism-based research, we summarize some targeted therapies which have been applied to the clinic or are currently under development. Furthermore, we posit that investigational drugs with different molecular targets may expand our horizon in anticancer therapy.
Highlights
Succinate was purified from amber in 1546 by a German chemist [1], and it rapidly became a major topic in biochemistry and bioenergetics studies [2]
Succinate dehydrogenase (SDH) is an enzyme complex that consists of SDHA, SDHB, SDHC and SDHD subunits, and catalyzes succinate into fumarate in the tricarboxylic acid cycle (TCA cycle) [3]
How does succinate facilitate tumorigenesis and progression? are there any effective targeting strategies to influence succinate signaling? In our opinion, accumulated succinate results in reprogramed metabolites, hypoxia inducible factor 1 (HIF-1) activation and stabilization, reactive oxygen species (ROS) production, tumor necrosis factor receptor-associated protein 1 (TRAP1) upregulation that leads to SDH inhibition, Nuclear related factor 2 (NRF2) pathway activation and tumor-promoting inflammation, all these are indispensable elements in oncogenesis and tumor progression
Summary
Succinate was purified from amber in 1546 by a German chemist [1], and it rapidly became a major topic in biochemistry and bioenergetics studies [2]. Researchers focused all their energy on its role in metabolism. Random mutation of SDH subunits by hereditary or acquired influences will contribute to the abnormal accumulation of succinate in the cytosol. In our opinion, accumulated succinate results in reprogramed metabolites, HIF-1 activation and stabilization, ROS production, tumor necrosis factor receptor-associated protein 1 (TRAP1) upregulation that leads to SDH inhibition, NRF2 pathway activation and tumor-promoting inflammation, all these are indispensable elements in oncogenesis and tumor progression. We discuss some mechanismbased research and illustrate several theoretically feasible strategies which aim at making a small contribution to targeted therapies in the clinic
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