Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine Synthesis and Survival in p53-Deficient Cancer Cells Exposed to Metabolic Stress

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. Significance: 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.

SOAT1 promotes mevalonate pathway dependency in pancreatic cancer

“…Additionally, GGPP is required for the synthesis of ubiquinone and dolichol (Hooff et al, 2010), and depletion of these metabolites may contribute to the proliferation defect observed. In support of this, a recent study demonstrated that inhibition of the mevalonate pathway induced apoptosis in p53-deficient colon cancer cells by decreasing ubiquinone levels, thereby impairing the synthesis of pyrimidine nucleotides (Kaymak et al, 2020). Finally, the incomplete rescue observed in cholesterol-replete media may be because excess cholesterol can induce cytotoxicity by generating ER stress (Fu et al, 2012;Maxfield and Tabas, 2005).…”

“…Negative feedback mechanisms maintain homeostasis in biological systems, and disruption of these regulatory mechanisms can trigger oncogenic transformation or drive malignant progression (Courtois-Cox et al, 2006;Zhao et al, 2015). Despite the stringent negative feedback exerted on the mevalonate pathway by unesterified cholesterol, mevalonate pathway genes are commonly up-regulated in cancer Kaymak et al, 2020;Moon et al, 2019;Turrell et al, 2017). How cancer cells escape cholesterol feedback inhibition to hyperactivate the mevalonate pathway is poorly understood.…”

“…Notably, the increased expression of mevalonate pathway genes is a feature of various cancer types (Carrer et al, 2019;Guillaumond et al, 2015;Kaymak et al, 2020;Moon et al, 2019;Turrell et al, 2017) and, in addition to PDAC (Li et al, 2016), SOAT1 has been implicated in the progression of prostate (Yue et al, 2014) and hepatocellular (Jiang et al, 2019) carcinomas. Therefore, the role of SOAT1 in enabling cancer cell evasion from cholesterol feedback inhibition could be a common targetable vulnerability in cancer.…”

“…The up-regulation of mevalonate pathway genes mediated by p53 loss or mutation has been shown to confer sensitivity to mevalonate pathway inhibition by statins in other cancer types Kaymak et al, 2020;Moon et al, 2019;Turrell et al, 2017). To determine whether increased dependency on the mevalonate pathway contributes to the differential sensitivity to SOAT1 loss in PDAC cells with p53 LOH compared with cells that retain WT p53, we treated T6 R172H/WT and T23 R172H/WT organoids and their matched p53 LOH counterparts with Simvastatin.…”

Integrated analysis of transcriptomic and metabolomic profiling reveal the p53 associated pathways underlying the response to ionizing radiation in HBE cells

“…Recently, increasing evidence has shown that cancer does not occur in mice with p53 mutations, which nonetheless retain p53 activity for regulation of energy metabolism; this suggests that p53 activities in the context of metabolic regulation may be critical for suppression of tumorigenesis [51]. Numerous cancer studies of the metabolic pathways regulated by p53 have been conducted recently [52][53][54]. As noted by Gomes et al in their review article, p53 activation is involved in the complex process of reprogramming cancer glucose metabolism [55].…”