Inborn and acquired metabolic defects in cancer

Abstract

The observation that altered metabolism is the fundamental cause of cancer was made by Otto Warburg nearly a century ago. However, the subsequent identification of oncogenes and tumor suppressor genes has displaced Warburg's theory pointing towards genetic aberrations as the underlining cause of cancer. Nevertheless, in the last decade, cancer-associated mutations have been identified in genes coding for tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) and closely related enzymes that have essential roles in cellular metabolism. These observations have revived interest in Warburg's hypothesis and prompted a flurry of functional studies in the hope of gaining mechanistic insight into the links between mitochondrial dysfunction, metabolic alterations, and cancer. In this review, we discuss the potential pro-oncogenic signaling role of some TCA cycle metabolites and their derivatives (oncometabolites). In particular, we focus on their effects on dioxygenases, a family of oxygen and α-ketoglutarate-dependent enzymes that control, among other things, the levels and activity of the hypoxia-inducible transcription factors and the activity of DNA and histone demethylases.

Fig. 1

The biochemistry and pathophysiology of oncometabolites accumulation in cancer. a Fumarate and succinate accumulate in the mitochondria and in the cytosol of cells expressing loss-of-function mutants of SDH or FH. 2-Hydroxyglutarate is accumulated as a consequence of neomorphic mutations in IDH1 in the cytosol and IDH2 in the mitochondria. b Biochemical effects of the accumulated oncometabolites in the cell. The effects are color coded: red for succinate, blue for fumarate, and green for 2HG. The accumulation of succinate impairs the enzymatic activity of several aKG-dependent dioxygenases: JMJd3, which regulates chromatin structure; PHD3, which is involved in promoting neuronal apoptosis in response to NGF withdrawal; and PHD2, which primarily regulates HIFα stability. Similarly, fumarate inhibits PHD2 enzymatic activity causing HIF stabilization. 2HG accumulation impairs DNA demethylation via the inhibition of the aKG-dependent dioxygenase TET2 and affects hematopoietic cells differentiation