Targeting glutamine metabolism in breast cancer with aminooxyacetate

Preethi Korangath, Wei Wen Teo, Helen Sadik, Liangfeng Han, Noriko Mori, Charlotte M. Huijts, Flonne Wildes, Santosh Bharti, Zhe Zhang, Cesar A. Santa-Maria, Hualing Tsai, Chi V. Dang, Vered Stearns, Zaver M. Bhujwalla, Saraswati Sukumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Purpose: Glutamine addiction in c-MYC-overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved. Experimental Design: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress-mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model. Results: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress-mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-mycoverexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy. Conclusions: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC-overexpressing breast cancers.

Original languageEnglish (US)
Pages (from-to)3263-3273
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Targeting glutamine metabolism in breast cancer with aminooxyacetate'. Together they form a unique fingerprint.

  • Cite this

    Korangath, P., Teo, W. W., Sadik, H., Han, L., Mori, N., Huijts, C. M., Wildes, F., Bharti, S., Zhang, Z., Santa-Maria, C. A., Tsai, H., Dang, C. V., Stearns, V., Bhujwalla, Z. M., & Sukumar, S. (2015). Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clinical Cancer Research, 21(14), 3263-3273. https://doi.org/10.1158/1078-0432.CCR-14-1200