Beyond the Warburg Effect: How Do Cancer Cells Regulate One-Carbon Metabolism?

Abstract

Altered metabolism in cancer cells is critical for tumor growth. One of the most notable aspects of this metabolic reprogramming lies in one-carbon metabolism. Cells require one-carbon units for nucleotide synthesis, methylation reactions, and for the generation of reducing cofactors. Therefore, the ability to rewire and fine-tune one-carbon metabolism is essential for the maintenance of cellular homeostasis. In this review, we describe how the major nutrient, energy, and redox sensors of the cell play a significant role in the regulation of flux through one-carbon metabolism to enable cell fate decisions. We will also discuss how dysregulated oncogenic signaling hijacks these regulatory mechanisms to support and sustain high rates of proliferation and cell survival essential for tumor growth.

Keywords: cancer; folate cycle; metabolic regulation; metabolic reprogramming; methionine cycle; one carbon metabolism.

Figure 1

One-carbon metabolism as a cellular process integrating nutrient status and availability. Glucose and amino acids input to the folate and methionine cycles (green) contributing with one-carbon units which can be used in anabolic synthesis of many building blocks, reducing species and co-factors (yellow). These synthesis products support a variety of cellular functions (gray) including synthesis of biomolecules, redox control and post-translational modification, sustaining cellular homeostasis.

Figure 2

Oncogenes and tumor suppressors manipulate regulation of one-carbon metabolism pathways in cancer to drive tumorigenesis. Sensors of nutrient and energy levels, mTOR and AMPK, and sensors of redox potential, HIF1 and NRF2, regulate the different steps in one-carbon metabolism to ensure proper flux. In cancers, oncogenes KEAP1, KRAS, and MYC, as well as tumor suppressors p53 and LKB1, manipulate these regulatory sensors, thus affecting the operation and flux of pathways within one-carbon metabolism and allowing for their hyperactivity to sustain uncontrolled proliferation and tumorigenesis.