Lipidome and metabolome analyses reveal metabolic alterations associated with MCF-7 apoptosis upon 4-hydroxytamoxifen treatment

  • Sci Rep. 2023 Oct 29;13(1):18549. doi: 10.1038/s41598-023-45764-2.
Kazuki Nishimoto  1 ,  Nobuyuki Okahashi  1  2  3 ,  Masaharu Maruyama  1 ,  Yoshihiro Izumi  4 ,  Kohta Nakatani  4 ,  Yuki Ito  2  5 ,  Junko Iida  2  5 ,  Takeshi Bamba  4 ,  Fumio Matsuda  6  7  8
Affiliations
  • 1. Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka, 565-0871, Japan.
  • 2. Department of Biotechnology, Osaka University Shimadzu Analytical Innovation Research Laboratory, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, 565-0871, Japan.
  • 3. Industrial Biotechnology Initiative Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, 565-0871, Japan.
  • 4. Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
  • 5. Analytical and Measuring Instruments Division, Shimadzu Corporation, 1 Nishinokyo Kuwabara-cho, Nakagyo-ku, Kyoto, 604-8511, Japan.
  • 6. Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka, 565-0871, Japan. [email protected].
  • 7. Department of Biotechnology, Osaka University Shimadzu Analytical Innovation Research Laboratory, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, 565-0871, Japan. [email protected].
  • 8. Industrial Biotechnology Initiative Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, 565-0871, Japan. [email protected].
PMID: 37899460 DOI: 10.1038/s41598-023-45764-2
Abstract

4-hydroxytamoxifen (OHT) is an anti-cancer drug that induces Apoptosis in breast Cancer cells. Although changes in lipid levels and mitochondrial respiration have been observed in OHT-treated cells, the overall mechanisms underlying these metabolic alterations are poorly understood. In this study, time-series metabolomics and lipidomics were used to analyze the changes in metabolic profiles induced by OHT treatment in the MCF-7 human breast Cancer cell line. Lipidomic and metabolomic analyses revealed increases in ceramide, diacylglycerol and triacylglycerol, and decreases in citrate, respectively. Gene expression analyses revealed increased expression of ATP-dependent citrate lyase (ACLY) and subsequent fatty acid biosynthetic Enzymes, suggesting that OHT-treated MCF-7 cells activate citrate-to-lipid metabolism. The significance of the observed metabolic changes was evaluated by co-treating MCF-7 cells with OHT and ACLY or a diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor. Co-treatment ameliorated cell death and reduced mitochondrial membrane potential compared to that in OHT treatment alone. The inhibition of cell death by co-treatment with an ACLY inhibitor has been observed in Other breast Cancer cell lines. These results suggest that citrate-to-lipid metabolism is critical for OHT-induced cell death in breast Cancer cell lines.

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