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

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Title: Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.
Authors: Geck, Renee C.1,2, Foley, Jackson R.3, Stewart, Tracy Murray3, Asara, John M.1, Casero Jr., Robert A.3, Toker, Alex1,2,4 atoker@bidmc.harvard.edu
Source: Journal of Biological Chemistry. 5/8/2020, Vol. 295 Issue 19, p6263-6277. 15p.
Subjects: Polyamines, Ornithine decarboxylase, Triple-negative breast cancer, Cancer cells, Cancer chemotherapy, Antineoplastic agents, Gene silencing
Abstract: 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 inODCwas mediated by its negative regulator antizyme, targetingODCto 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. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
An: 143256966
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  Data: Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.
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  Data: <searchLink fieldCode="AR" term="%22Geck%2C+Renee+C%2E%22">Geck, Renee C.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Foley%2C+Jackson+R%2E%22">Foley, Jackson R.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Stewart%2C+Tracy+Murray%22">Stewart, Tracy Murray</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Asara%2C+John+M%2E%22">Asara, John M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Casero+Jr%2E%2C+Robert+A%2E%22">Casero Jr., Robert A.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Toker%2C+Alex%22">Toker, Alex</searchLink><relatesTo>1,2,4</relatesTo><i> atoker@bidmc.harvard.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 5/8/2020, Vol. 295 Issue 19, p6263-6277. 15p.
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  Data: <searchLink fieldCode="DE" term="%22Polyamines%22">Polyamines</searchLink><br /><searchLink fieldCode="DE" term="%22Ornithine+decarboxylase%22">Ornithine decarboxylase</searchLink><br /><searchLink fieldCode="DE" term="%22Triple-negative+breast+cancer%22">Triple-negative breast cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cells%22">Cancer cells</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+chemotherapy%22">Cancer chemotherapy</searchLink><br /><searchLink fieldCode="DE" term="%22Antineoplastic+agents%22">Antineoplastic agents</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+silencing%22">Gene silencing</searchLink>
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  Data: 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 inODCwas mediated by its negative regulator antizyme, targetingODCto 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1074/jbc.RA119.012376
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      – Code: eng
        Text: English
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        PageCount: 15
        StartPage: 6263
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      – SubjectFull: Polyamines
        Type: general
      – SubjectFull: Ornithine decarboxylase
        Type: general
      – SubjectFull: Triple-negative breast cancer
        Type: general
      – SubjectFull: Cancer cells
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      – SubjectFull: Cancer chemotherapy
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      – SubjectFull: Antineoplastic agents
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      – SubjectFull: Gene silencing
        Type: general
    Titles:
      – TitleFull: Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.
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            NameFull: Asara, John M.
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              Text: 5/8/2020
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              Y: 2020
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