Proline Synthesis Through PYCR1 is Required to Support Cancer Cell Proliferation and Survival in Oxygen-Limiting Conditions

The demands of cancer cell proliferation alongside an inadequate angiogenic response leads to insufficient oxygen availability in the tumour microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing activity of the tricarboxylic acid (TCA) cycle and mitochondrial respiration are functionally linked. As the oxidising activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show here that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidising NADH with proline synthesised as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting oxygen-sparing TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.