Cancer cells acquire metabolic reprogramming to satisfy their high biogenetic demands, but little is known about how metabolic remodeling enables cancer cells to survive stress associated with genomic instability. Here, we show that the mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) is transcriptionally suppressed by p53, and its up-regulation by p53 inactivation leads to increased folate metabolism, de novo purine synthesis, and tumor growth in vivo and in vitro. Moreover, MTHFD2 unexpectedly promotes nonhomologous end joining in response to DNA damage by forming a complex with PARP3 to enhance its ribosylation, and the introduction of a PARP3-binding but enzymatically inactive MTHFD2 mutant (e.g., D155A) sufficiently prevents DNA damage. Notably, MTHFD2 depletion strongly restrains p53-deficient cell proliferation and sensitizes cells to chemotherapeutic agents, indicating a potential role for MTHFD2 depletion in the treatment of p53-deficient tumors.

Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth. Implications: By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.

Cancer cells exhibit altered and elevated metabolic processes to meet their increased bioenergetic and biosynthetic demands, leading to the production of ammonia as a byproduct. However, the mechanisms by which tumor cells manage excess ammonia remain poorly understood, despite its critical role in nitrogen metabolism. The urea cycle (UC), a central pathway for ammonia detoxification, has been insufficiently explored in the context of cancer metabolism. In this study, we identify Forkhead box O1 (FOXO1), a transcription factor essential for tumorigenesis and progression, as a key regulator of the UC in breast cancer cells. Specifically, FOXO1 inhibits argininosuccinate lyase (ASL) expression, a crucial enzyme in the UC, leading to reduced ammonia detoxification. Mechanistic analyses reveal that ASL is a direct transcriptional target of FOXO1. Functionally, we demonstrate that FOXO1 modulates the migratory ability of breast cancer cells through the regulation of ASL and arginine metabolism. These findings unveil an unexpected role of FOXO1 in regulating the UC in tumors and highlight a novel mechanism by which breast cancer cells exploit metabolic pathways to support their progression and metastasis. Our study provides valuable insights into cancer metabolism and identifies potential targets for therapeutic intervention.

Metabolic adaptability, controlled by transcription factors or oncogenes, is critical for the survival of cancer cells. However, the mechanism by which the transcription factor forkhead box protein O1 (FOXO1) regulates the proliferation and survival of malignant tumor cells under high levels of reactive oxygen species (ROS) remains poorly understood. Here, we found that FOXO1 endows cancer cells with the strong antioxidative capacity and rapid proliferation. By upregulating the expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, FOXO1 promotes the synthesis of nicotinamide adenine dinucleotide phosphate and ribose 5-phosphate and thus enhances the antioxidative and proliferative capabilities of cancer cells. Induction of G6PD expression in FOXO1-deficient cells mitigates tumor growth inhibition and alleviates ROS level elevation. These results establish a critical role of FOXO1 in the regulation of G6PD during the antioxidative and proliferative processes of cancer cells.