Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

McGregor, Grace H.; Campbell, Andrew D.; Fey, Sigrid K.; Tumanov, Sergey; Sumpton, David; Blanco, Giovanny Rodriguez; Mackay, Gillian; Nixon, Colin; Vázquez, Alexei; Sansom, Owen J.; Kamphorst, Jurre J.

doi:10.1158/0008-5472.can-19-0644

Cited by 95 publications

(71 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because AMP-activated protein kinase (AMPK) activation by agonists, such as aspirin or metformin, blocks this feedback on HMGCR, a combination treatment combining aspirin or metaformin with fluvastatin has been found to almost completely abrogate the colonization capability of breast cancer cells 124 . In another recent study, statin treatment has been found to significantly decrease levels of the mevalonate-pathway product coenzyme Q in cancer cells, thus leading to excessive oxidative stress 125 . Given that cancer cells can upregulate antioxidant pathways by enhancing cystine import and consequently decrease oxidative stress, the use of AZD6244an inhibitor of mitogen-activated protein kinase kinase (MEK), which limits cystine import-in combination with statins has been shown to be highly cytotoxic in cancer cells 125 .…”

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 95%

“…In another recent study, statin treatment has been found to significantly decrease levels of the mevalonate-pathway product coenzyme Q in cancer cells, thus leading to excessive oxidative stress 125 . Given that cancer cells can upregulate antioxidant pathways by enhancing cystine import and consequently decrease oxidative stress, the use of AZD6244an inhibitor of mitogen-activated protein kinase kinase (MEK), which limits cystine import-in combination with statins has been shown to be highly cytotoxic in cancer cells 125 .…”

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 95%

See 1 more Smart Citation

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

View full text Add to dashboard Cite

C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

show abstract

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 95%

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 95%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

View full text Add to dashboard Cite

show abstract

“…This was achieved by crossing mice carrying conditional alleles of Apc or an activated allele of Kras (Apc fl/fl or Apc fl/fl ; Kras G12D/þ ) to mice bearing the VillinCre ERT2 transgene (37). After induction of CRE-dependent recombination, mice were treated for 4 days with simvastatin or vehicle and with D 2 O to assess cholesterol and ubiquinone synthesis in vivo (38). Histologic analysis of BrdU-positive cells demonstrated that simvastatin had no effect on proliferation in Apc-deficient intestinal crypts, but blocked hyperproliferation induced by Kras activation (Fig.…”

Section: The Metabolic Output Of the Mevalonate Pathway Depends On Enmentioning

confidence: 99%

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

Kaymak¹,

Maier²,

Schmitz³

et al. 2020

Cancer Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Cells were washed with ice-cold PBS and metabolites were extracted with 1:9 (v/v) water: methanol buffer and 20 µl lathosterol (100 ng/µl) was added as an internal standard. Saponification to obtain the total cholesterol pool and subsequent GC-MS analysis was carried out as in McGregor et al 85 .…”

Section: Cholesterol Extraction and Gc-ms Analysismentioning

confidence: 99%

“…Subsequent chloroform extraction of lipids and LC-MS analysis were carried out as in McGregor et al 85 .…”

Section: Trans-fatty Acid Extraction and Lc-ms Analysismentioning

confidence: 99%

PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

Kay

Paterson

Domingo

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The extracellular matrix (ECM) is the central driver of the desmoplastic reaction that fosters cancer aggressiveness. Cancer associated fibroblasts (CAFs) are the major source of ECM in tumours, thus being the optimal target to limit deposition of pro-tumourigenic ECM to oppose cancer. CAFs are metabolically active cells, however, how they support the biosynthetic requirements of producing ECM, and whether this can be targeted to influence tumour progression has not been investigated.We found that the pyruvate dehydrogenase kinase 2 (PDK2), a major inhibitor of the pyruvate dehydrogenase complex (PDC), is highly downregulated in CAFs and in the tumour stroma, when compared to normal fibroblasts. As consequence, PDC is more activated and generates acetyl-CoA, which elicits an epigenetic reprogramming through the histone acetyl transferase P300/CBP. This epigenetic reprogramming drives increased ECM production through increasing transcription of collagen genes and proline synthesis. We found that increased proline availability is necessary to support the biosynthetic requirements that follow the epigenetic reprogramming, for the translation of collagen to make abundant ECM. Targeting the rate-limiting enzyme for proline synthesis, pyrroline-5-carboxylate reductase 1 (PYCR1), in CAFs was sufficient to limit collagen deposition and hamper tumour growth. In conclusion, ECM production in CAFs is under strict metabolic control, and our results warrant considering targeting proline synthesis to normalise ECM production in tumours and possibly other diseases involving collagen production, such as fibrosis.

show abstract

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

Cited by 95 publications

References 63 publications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

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

PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

Contact Info

Product

Resources

About