Deguelin inhibits vasculogenic function of endothelial progenitor cells in tumor progression and metastasis via suppression of focal adhesion

Abstract

Deguelin is a nature-derived chemopreventive drug. Endothelial progenitor cells (EPCs) are bone-marrow (BM)-derived key components to induce new blood vessels in early tumorigenesis and metastasis. Here we determined whether deguelin inhibits EPC function in vitro and in vivo at doses not affecting cancer cell apoptosis. Deguelin significantly reduced the number of EPC colony forming units of BM-derived c-kit+/sca-1+ mononuclear cells (MNCs), proliferation, migration, and adhesion to endothelial cell monolayers, and suppressed incorporation of EPC into tube-like vessel networks when co-cultured with endothelial cells. Deguelin caused cell cycle arrest at G1 without induction of apoptosis in EPC. In a mouse tumor xenograft model, tumor growth, lung metastasis and tumor-induced circulating EPCs were supressed by deguelin treatment (2 mg/kg). In mice tranplanted with GFP-expressing BM-MNCs, deguelin reduced the co-localization of CD31 and GFP, suggesting suppression of BM-derived EPC incoporation into tumor vessels. Interestingly, focal adhesion kinase (FAK)-integrin-linked kinase (ILK) activation and actin polymerization were repressed by deguelin. Decreased number of focal adhesions and a depolarized morphology was found in deguelin-treated EPCs. Taken together, our results suggest that the deguelin inhibits tumorigenesis and metastasis via EPC suppression and that suppression of focal adhesion by FAK-integrin-ILK-dependent actin remodeling is a key underlying molecular mechanism.

Deguelin inhibits non-small cell lung cancer via down-regulating Hexokinases II-mediated glycolysis

“…We confirmed through this study that HK2 is overexpressed in NSCLC cell lines and lung cancer tissues (Figure 1), which implied that HK2 may has a crucial role during lung tumorgenesis. Recently, some natural compounds, such as resveratrol [39] and EGCG [40, 41], have been demonstrated to inhibit hepatocellular carcinoma or oral cancer via directly targeting glycolysis. These findings implied that decreases of glycolysis or inhibits of metabolic enzymes may act as one of the major mechanisms in natural compound mediated anti-tumor activities.…”

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

“…However, the protagonists of inter-cellular adhesion are not yet identified in the here presented 3D model. Whether NF-kB and ICAM-1 establish CRC-CAF adhesion, as shown to be the case in 12(S)-HETE-triggered breast cancer/EC intravasation [14, 19], needs to be investigated in future studies.…”

“…However, the induction of MLC2 phosphorylation and CCID formation is not exclusively caused by the 12(S)-HETE gradient, as there are also other factors prompting tropism and retraction i.e. MMP1, which induces Ca 2+ release and MLC2 activation in ECs as well [19, 46]. Yet, treating the CRC/CAF model with the pan-matrix metalloprotease inhibitor GM6001 did not inhibit the formation of CCIDs (data not shown).…”

“…Apparently, cancer cells can co-opt this property as cancer cell-secreted 12(S)-HETE activates MLC2 in lymph endothelial cells as a prerequisite for endothelial junction retraction and formation of CCIDs [5, 17–19]. …”

Promoting vascular repair in the retina: can stem/progenitor cells help?

“…In particular, one study has found that deguelin, a chemopreventive drug, can reduce the number of colony-forming units of bone marrow-derived c-Kit + /Sca-1 + mononuclear cell migration, adhesion, and proliferation capability. When cocultured with endothelial cells, the treated EPC were less likely to form tubelike vessels, because deguelin arrested the cells at the G 1 checkpoint 42. In Moyamoya disease (MMD), a form of childhood stroke, the expression of retinaldehyde dehydrogenase 2 is significantly reduced in ECFCs, rendering them less efficient in forming capillary networks in vitro as well as in vivo 43.…”