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.
Keywords: GPR91; HIF; SDH; succinate; tumorigenesis.