journal contribution
posted on 2023-03-31, 03:26 authored by Irem Kaymak, Carina R. Maier, Werner Schmitz, Andrew D. Campbell, Beatrice Dankworth, Carsten P. Ade, Susanne Walz, Madelon Paauwe, Charis Kalogirou, Hecham Marouf, Mathias T. Rosenfeldt, David M. Gay, Grace H. McGregor, Owen J. Sansom, Almut Schulze (1) Figure S1 shows Metabolic flux analysis of p53+/+ and p53-/- cells in monolayer and spheroid culture. (2) Figure S2 shows Mechanism of induction of SREBP2 target genes in p53-deficient spheroid cultures. (3) Figure S3 shows Induction of cell cycle arrest and apoptosis by simvastatin in spheroid cultures. (4) Figure S4 shows Blockade of cholesterol and ubiquinone synthesis by statins. (5) Figure S5 shows Effect of simvastatin on TCA cycle flux and failure of ubiquinone to restore viability in monolayer cells. (6) Figure S6 shows Inhibition of apoptosis in p53-deficient spheroid cultures by uridine. (7) Figure S7 shows Genotyping of cells used for organoid cultures and lack of effect of leflunomide on intestinal hyperproliferation.
Funding
German Research Foundation
Graduate School of Life Sciences Würzburg
Cancer Research UK
History
ARTICLE ABSTRACT
Oncogene activation and loss of tumor suppressor function changes the metabolic activity of cancer cells to drive unrestricted proliferation. Moreover, cancer cells adapt their metabolism to sustain growth and survival when access to oxygen and nutrients is restricted, such as in poorly vascularized tumor areas. We show here that p53-deficient colon cancer cells exposed to tumor-like metabolic stress in spheroid culture activated the mevalonate pathway to promote the synthesis of ubiquinone. This was essential to maintain mitochondrial electron transport for respiration and pyrimidine synthesis in metabolically compromised environments. Induction of mevalonate pathway enzyme expression in the absence of p53 was mediated by accumulation and stabilization of mature SREBP2. Mevalonate pathway inhibition by statins blocked pyrimidine nucleotide biosynthesis and induced oxidative stress and apoptosis in p53-deficient cancer cells in spheroid culture. Moreover, ubiquinone produced by the mevalonate pathway was essential for the growth of p53-deficient tumor organoids. In contrast, inhibition of intestinal hyperproliferation by statins in an Apc/KrasG12D-mutant mouse model was independent of de novo pyrimidine synthesis. Our results highlight the importance of the mevalonate pathway for maintaining mitochondrial electron transfer and biosynthetic activity in cancer cells exposed to metabolic stress. They also demonstrate that the metabolic output of this pathway depends on both genetic and environmental context.
These findings suggest that p53-deficient cancer cells activate the mevalonate pathway via SREBP2 and promote the synthesis of ubiquinone that plays an essential role in reducing oxidative stress and supports the synthesis of pyrimidine nucleotide.
