Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

Booher, Keith; Lin, Dawei; Borrego, Stacey L.; Kaiser, Peter

doi:10.4161/cc.22767

Cited by 27 publications

(62 citation statements)

References 34 publications

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“…6B). We have previously demonstrated that there are decreased levels of the DNA replication factor Cdc6 as a result of SAM checkpoint activation in the human breast cancer cell line MDA-MB 468 (Booher et al, 2012). Consistent with that study, Cdc6 levels were also decreased in FL5.12 cells during SAM depletion, and this phenotype could be partially reversed by treatment with the p38 inhibitor SB202190 (supplementary material Fig.…”

Section: Q99lsupporting

confidence: 73%

“…3C). This is in contrast to previous results obtained with MDA-MB468 breast cancer cells where cyclin E levels remained high during methionine stress (Booher et al, 2012). This is probably due to dysregulation of cyclin E in these breast cancer cells owing to mutations in cyclin E regulators.…”

Section: Sam Depletion Blocks Entry Into S Phase Despite High Cdk4 Accontrasting

confidence: 56%

“…Interestingly, addiction of cancer cells to a high flux through the methionine metabolism pathway has been known for over 35 years (Halpern et al, 1974). Recent studies in breast cancer cells suggest that SAM rather than methionine might be the limiting metabolite defining addiction to this metabolic pathway (Booher et al, 2012). Consistent with this idea, targeting methionine adenosyltransferase (MAT) with either a small molecule inhibitor or shRNA induces apoptosis in leukemia cells (Attia et al, 2008;Jani et al, 2009).…”

Section: Discussionmentioning

confidence: 49%

“…Consistent with this idea, targeting methionine adenosyltransferase (MAT) with either a small molecule inhibitor or shRNA induces apoptosis in leukemia cells (Attia et al, 2008;Jani et al, 2009). The mechanisms of how cells induce cell cycle arrest and apoptosis in response to SAM limitation is currently unknown, but experiments in the yeast and breast cancer cell models indicate loss of pre-replication complexes from chromatin as a contributing factor (Booher et al, 2012;Su et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this notion, targeted inhibition of MAT with a chemical inhibitor or shRNA knockdown was shown to inhibit leukemia cell proliferation and induce apoptosis (Attia et al, 2008;Jani et al, 2009), suggesting not only the existence of a SAM checkpoint in mammalian cells but also its potential as a therapeutic target. Furthermore, recent reports indicate breast and prostate cancer cells suffer a G1 cell cycle arrest when cultured in medium where methionine is replaced with its metabolic precursor homocysteine (Booher et al, 2012;Lu and Epner, 2000), probably as a consequence of reduced flux through the homocysteinemethionine-SAM metabolic axis, which results in insufficient SAM to support cell cycle progression (Booher et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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S-adenosylmethionine limitation induces p38 mitogen activated protein kinase and triggers cell cycle arrest in G1

Lin

Chung

Kaiser

2013

Journal of Cell Science

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The primary methyl group donor S-adenosylmethionine (SAM) is important for a plethora of cellular pathways including methylation of nucleic acids, proteins, and the 59 cap structure of mRNAs, as well as biosynthesis of phospholipids and polyamines. In addition, because it is the cofactor for chromatin methylation, SAM is an important metabolite for the establishment and maintenance of epigenetic marks. Here, we demonstrate that cells halt proliferation when SAM levels become low. Cell cycle arrest occurs primarily in the G1 phase of the cell cycle and is accompanied by activation of the mitogen-activated protein kinase p38 (MAPK14) and subsequent phosphorylation of MAPK-activated protein kinase-2 (MK2). Surprisingly, Cdk4 activity remains high during cell cycle arrest, whereas Cdk2 activity decreases concomitantly with cyclin E levels. Cell cycle arrest was induced by both pharmacological and genetic manipulation of SAM synthesis through inhibition or downregulation of methionine adenosyltransferase, respectively. Depletion of methionine, the precursor of SAM, from the growth medium induced a similar cell cycle arrest. Unexpectedly, neither methionine depletion nor inhibition of methionine adenosyltransferase significantly affected mTORC1 activity, suggesting that the cellular response to SAM limitation is independent from this major nutrient-sensing pathway. These results demonstrate a G1 cell cycle checkpoint that responds to limiting levels of the principal cellular methyl group donor S-adenosylmethionine. This metabolic checkpoint might play important roles in maintenance of epigenetic stability and general cellular integrity.

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Section: Q99lsupporting

confidence: 73%

Section: Sam Depletion Blocks Entry Into S Phase Despite High Cdk4 Accontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

S-adenosylmethionine limitation induces p38 mitogen activated protein kinase and triggers cell cycle arrest in G1

Lin

Chung

Kaiser

2013

Journal of Cell Science

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Isolation and Characterization of Methionine-Independent Clones from Methionine-Dependent Cancer Cells

Borrego¹,

Lin²,

Kaiser³

2019

Methods in Molecular Biology

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Amino acid metabolism as a therapeutic target in cancer: a review

2021

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Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.

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Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

Cited by 27 publications

References 34 publications

S-adenosylmethionine limitation induces p38 mitogen activated protein kinase and triggers cell cycle arrest in G1

S-adenosylmethionine limitation induces p38 mitogen activated protein kinase and triggers cell cycle arrest in G1

Isolation and Characterization of Methionine-Independent Clones from Methionine-Dependent Cancer Cells

Amino acid metabolism as a therapeutic target in cancer: a review

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