Arginine: Challenges and opportunities of this two-faced molecule in cancer therapy

Jahani, Mozhgan; Noroznezhad, Fatemeh; Mansouri, Kamran

doi:10.1016/j.biopha.2018.02.109

Cited by 51 publications

(38 citation statements)

References 65 publications

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“…For 13 C-labeled experiments, five microliters from each sample (20 uL) were injected with similar methodology as above using a 6500 QTRAP (AB/SCIEX) and integrated using MultiQuant v3.0 software (70). SRMs were created for expected 13 C incorporation in various forms. Metabolite total ion counts were the integrated total ion current from a single SRM transition and normalized by cellular protein content.…”

Section: Lc/ms-ms Metabolomics Profilingmentioning

confidence: 99%

“…Furthermore, arginine plays an important role in the immune system, as it is required for full activation of natural killer and T-cells (11,12). A number of studies aimed at targeting arginine metabolism have focused on arginine auxotroph tumors, since they are sensitive to arginine depletion (13,14). However, less than 10% of breast tumors lack the rate-limiting arginine synthesis enzyme argininosuccinate synthase (ASS1) (15).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Geck

Foley

Murray-Stewart

et al. 2020

Journal of Biological Chemistry

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Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

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Section: Lc/ms-ms Metabolomics Profilingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Geck

Foley

Murray-Stewart

et al. 2020

Journal of Biological Chemistry

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show abstract

“…Many cancers, in particular, lymphomas, melanoma, mesothelioma, and hepatocellular, renal cell, and prostate carcinomas that are otherwise chemoresistant and with poor clinical outcome, exhibit decreased expression of arginine metabolizing enzymes including argininosuccinate synthetase (ASS1) and/or ornithine transcarbamylase (OTC) and are thus auxotrophic for arginine (74). Deprivation of circulating arginine via enzymes such as arginase, arginine deiminase (ADI), and arginine decarboxylase (ADC) exploits a significant metabolic vulnerability of cancer cells in these tumor types, and such enzyme-mediated arginine depletion is currently under clinical investigation along multiple fronts to advance this potential class of anticancer therapeutics (75)(76)(77). While positive results have been reported in this regard, the role of arginine in tumors in general is multidimensional.…”

Section: Arginine Metabolismmentioning

confidence: 99%

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer

2020

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The observation that cancer acquires significant changes in its metabolism dates back nearly a century, to Otto Warburg noting that cancer cells preferentially utilize glycolysis even when there are no hypoxic conditions in the growth media. Altered energetics are thus considered a hallmark of cancer. However, it has become clear that altered metabolism is not limited to cellular energetic pathways. Alterations in amino acid synthesis and catabolism, lipid biogenesis, and other pathways such as polyamine processing are commonly seen in cancer. Additionally, alterations in metabolism do not only have profound effects for cancer cells but also affect their surrounding microenvironment. With new cancer therapeutics targeting the immune microenvironment, these effects may have implications on cancer growth and response to therapy. These interactions are profound in lung cancer, further demonstrating the manifold interactions between developing tumors and the inflammatory microenvironment. Here, we discuss how dysregulation of metabolism in cancer alters its microenvironment and how this newfound knowledge can be exploited for anticancer treatment.

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“…Furthermore, arginine plays an important role in the immune system, as it is required for full activation of natural killer and T-cells (9,10). A number of studies aimed at targeting arginine metabolism have focused on arginine auxotroph tumors, since they are sensitive to arginine depletion (11,12). However, less than 10% of breast tumors lack the rate-limiting arginine synthesis enzyme argininosuccinate synthase (ASS1) (13).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Geck

Foley

Murray-Stewart

et al. 2020

Preprint

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Treatment of triple-negative breast cancer (TNBC) is limited by a lack of effective molecular targeted therapies. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. We found that exposure of TNBC cells to cytotoxic chemotherapy drugs leads to alterations in arginine and polyamine metabolites due to a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase (ODC). The reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor DFMO sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines showed greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. Alterations in polyamine metabolism in response to chemotherapy, as well as preferential sensitization of TNBC cells to chemotherapy by DFMO, suggest that ODC may be a targetable metabolic vulnerability in TNBC.

show abstract

Arginine: Challenges and opportunities of this two-faced molecule in cancer therapy

Cited by 51 publications

References 65 publications

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

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