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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Low-dose metronomic doxorubicin inhibits mobilization and differentiation of endothelial progenitor cells through REDD1-mediated VEGFR-2 downregulation

  • Park, Minsik (Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine) ;
  • Kim, Ji Yoon (Department of Anaesthesiology and Pain Medicine, Hanyang University Hospital) ;
  • Kim, Joohwan (Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine) ;
  • Lee, Jeong-Hyung (Department of Biochemistry, Kangwon National University) ;
  • Kwon, Young-Guen (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Kim, Young-Myeong (Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine)
  • Received : 2021.07.19
  • Accepted : 2021.08.10
  • Published : 2021.09.30
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Abstract

Low-dose metronomic chemotherapy has been introduced as a less toxic and effective strategy to inhibit tumor angiogenesis, but its anti-angiogenic mechanism on endothelial progenitor cells (EPCs) has not been fully elucidated. Here, we investigated the functional role of regulated in development and DNA damage response 1 (REDD1), an endogenous inhibitor of mTORC1, in low-dose doxorubicin (DOX)-mediated dysregulation of EPC functions. DOX treatment induced REDD1 expression in bone marrow mononuclear cells (BMMNCs) and subsequently reduced mTORC1-dependent translation of endothelial growth factor (VEGF) receptor (Vegfr)-2 mRNA, but not that of the mRNA transcripts for Vegfr-1, epidermal growth factor receptor, and insulin-like growth factor-1 receptor. This selective event was a risk factor for the inhibition of BMMNC differentiation into EPCs and their angiogenic responses to VEGF-A, but was not observed in Redd1-deficient BMMNCs. Low-dose metronomic DOX treatment reduced the mobilization of circulating EPCs in B16 melanoma-bearing wild-type but not Redd1-deficient mice. However, REDD1 overexpression inhibited the differentiation and mobilization of EPCs in both wild-type and Redd1-deficient mice. These data suggest that REDD1 is crucial for metronomic DOX-mediated EPC dysfunction through the translational repression of Vegfr-2 transcript, providing REDD1 as a potential therapeutic target for the inhibition of tumor angiogenesis and tumor progression.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2017R1A2B3004565).

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