Related Experiment Video
Updated: Oct 15, 2025
Chemotherapy-induced Vascular Toxicity - Real-time In vivo Imaging of Vessel Impairment
Published on: January 7, 2015
REDD1 is a determinant of low-dose metronomic doxorubicin-elicited endothelial cell dysfunction through
Minsik Park1, Joohwan Kim1, Taesam Kim1
1Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, 24341, Republic of Korea.
Abstract:
Low-dose metronomic chemotherapy (LDMC) inhibits tumor angiogenesis and growth by targeting tumor-associated endothelial cells, but the molecular mechanism has not been fully elucidated. Here, we examined the functional role of regulated in development and DNA damage responses 1 (REDD1), an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in LDMC-mediated endothelial cell dysfunction. Low-dose doxorubicin (DOX) treatment induced REDD1 expression in cultured vascular and lymphatic endothelial cells and subsequently repressed the mRNA expression of mTORC1-dependent translation of vascular endothelial growth factor receptor (Vegfr)-2/3, resulting in the inhibition of VEGF-mediated angiogenesis and lymphangiogenesis. These regulatory effects of DOX-induced REDD1 expression were additionally confirmed by loss- and gain-of-function studies. Furthermore, LDMC with DOX significantly suppressed tumor angiogenesis, lymphangiogenesis, vascular permeability, growth, and metastasis in B16 melanoma-bearing wild-type but not Redd1-deficient mice. Altogether, our findings indicate that REDD1 is a crucial determinant of LDMC-mediated functional dysregulation of tumor vascular and lymphatic endothelial cells by translational repression of Vegfr-2/3 transcripts, supporting the potential therapeutic properties of REDD1 in highly progressive or metastatic tumors.
Insights
Low-dose metronomic chemotherapy uses regulated in development and DNA damage responses 1 (REDD1) to inhibit tumor growth. REDD1 represses vascular endothelial growth factor receptor (VEGFR) expression, reducing angiogenesis and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Low-dose metronomic chemotherapy (LDMC) inhibits tumor angiogenesis and growth.
- The precise molecular mechanisms underlying LDMC's effects on endothelial cells are not fully understood.
- Regulated in development and DNA damage responses 1 (REDD1) is an inhibitor of mammalian target of rapamycin complex 1 (mTORC1).
Purpose of the Study:
- To investigate the functional role of REDD1 in LDMC-induced endothelial cell dysfunction.
- To elucidate the molecular pathway through which LDMC affects angiogenesis and lymphangiogenesis.
- To assess the therapeutic potential of targeting REDD1 in cancer treatment.
Main Methods:
- Treatment of cultured endothelial cells with low-dose doxorubicin (DOX).
- Analysis of REDD1 and mTORC1 signaling pathway components.
- Loss- and gain-of-function studies to evaluate REDD1's role.
- In vivo studies using B16 melanoma xenografts in wild-type and Redd1-deficient mice.
Main Results:
- Low-dose doxorubicin (DOX) treatment increased REDD1 expression in endothelial cells.
- REDD1 repressed the mRNA expression of vascular endothelial growth factor receptor (VEGFR)-2/3, inhibiting mTORC1-dependent translation.
- DOX-induced REDD1 suppressed tumor angiogenesis, lymphangiogenesis, vascular permeability, growth, and metastasis in vivo.
- These effects were dependent on REDD1 expression, as Redd1-deficient mice showed suppressed responses.
Conclusions:
- REDD1 is a critical mediator of LDMC-induced endothelial cell dysfunction.
- REDD1 functions by translationally repressing VEGFR-2/3 transcripts, thereby inhibiting angiogenesis and lymphangiogenesis.
- REDD1 holds potential as a therapeutic target for progressive or metastatic tumors.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...