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.
Highlights
Growing solid tumors have a hypoxic environment due to an imbalance between oxygen supply and consumption, which in turn stimulates hypoxia-dependent expression of angiogenic and lymphangiogenic genes, including vascular endothelial growth factor (VEGF)[1]
Chemotherapeutic drugs induce REDD1 and downregulate VEGFR-2/3 expression To address the possible link between inhibition of tumor angiogenesis and increased REDD1 expression by LDMC3,7, we treated human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) with noncytotoxic low-dose DOX (3 nM), whose concentration was determined by MTT-based mitochondrial activity and lactate dehydrogenase release assays (Supplementary Fig. 1a, b), and found a significant upregulation of REDD1 at the mRNA and protein levels (Fig. 1a, b)
REDD1 overexpression led to a prominent decrease in the vascular endothelial growth factor receptor (Vegfr)-2/3 mRNA levels and a partial decrease in EphB4 mRNA expression but did not affect the mRNA levels of other angiogenesis-related receptors, including Vegfr-1, in the highmolecular-weight polysomal fraction compared with total mRNA expression (Fig. 1c)
Summary
Growing solid tumors have a hypoxic environment due to an imbalance between oxygen supply and consumption, which in turn stimulates hypoxia-dependent expression of angiogenic and lymphangiogenic genes, including vascular endothelial growth factor (VEGF)[1]. Solid tumor growth is typically accompanied by angiogenesis and lymphangiogenesis via stimulation of VEGF receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3 on tumorassociated endothelial cells (TECs), subsequently improving energy metabolism, proliferation, and metastasis of tumor cells[2]. Conventional chemotherapy at the maximal tolerated dose (MTD) results in impressive therapeutic responses against tumor cells[3] but can cause severe adverse effects, such vomiting, hair loss, cardiotoxicity, and drug resistance[3]. Low-dose metronomic chemotherapy (LDMC) has been developed as a promising alternative strategy to avoid or minimize the side effects of MTD chemotherapy. The therapeutic effects of LDMC are associated with an increased sensitivity of activated TECs compared with other types of normal cells and tumor cells[3,4,5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
