CUL5 is required for thalidomide-dependent inhibition of cellular proliferation

Abstract

Angiogenesis is essential for cancer metastasis, thus the discovery and characterization of molecules that inhibit this process is important. Thalidomide is a teratogenic drug which is known to inhibit angiogenesis and effectively inhibit cancer metastasis, yet the specific cellular targets for its effect are not well known. We discovered that CUL5 (previously identified as VACM-1), a scaffold protein in E3 ligase complexes, is involved in thalidomide-dependent inhibition of endothelial cell growth. Our results show that in human endothelial cells (HUVEC), thalidomide-dependent decrease in cell growth was associated with decreased nuclear localization of CUL5. In HUVEC transfected with anti-VACM-1 siRNA, thalidomide failed to decrease cell growth. Previously it was established that the antiproliferative effect of CUL5 is inhibited in rat endothelial cells (RAMEC) transfected with mutated CUL5 which is constitutively modified by NEDD8, a ubiquitin-like protein. In this study, the antiproliferative response to thalidomide was compromised in RAMEC expressing mutated CUL5. These results suggest that CUL5 protein is involved in the thalidomide-dependent regulation of cellular proliferation in vitro. Consequently, CUL5 may be an important part of the mechanism for thalidomide-dependent inhibition of cellular proliferation, as well as a novel biomarker for predicting a response to thalidomide for the treatment of disorders such as multiple myeloma and HIV infection.

CUL5-Mediated Visfatin (NAMPT) Degradation Blocks Endothelial Proliferation and Angiogenesis via the MAPK/PI3K-AKT Signaling

“…CUL5 has been previously reported to mediate the role of thalidomide in inhibiting endothelial cell proliferation and neovascularization by participating in the inhibition of MAPK phosphorylation and other pathways. 28,45 According to Mentha and BioGrid databases, CUL5 may interact with NAMPT, which was then confirmed by Co-IP analysis. Through interacting with NAMPT and decreasing NAMPT protein levels, CUL5 overexpression exerted opposite effects on H 2 O 2 -stimulated HCAECs, that is, further enhanced H 2 O 2 -induced HCAEC dysfunction.…”

ERp29 counteracts the suppression of malignancy mediated by endoplasmic reticulum stress and promotes the metastasis of colorectal cancer

“…The candidate proteins were CUL5, SSR4, RPA2 and TBCA, and their expressions were verified using RT-qPCR and western blotting (data not shown). CUL5, as a scaffolding protein in E3 ligase complexes, is functionally involved in numerous cellular activities including cell growth, cell cycle, apoptosis and cancer cell invasion (31–35). The present study therefore investigated whether CUL5 was able to confer the synergistic effect of ERp29 to regulate the biological behavior of tumor cells.…”

Cullin 5 is a novel candidate tumor suppressor in renal cell carcinoma involved in the maintenance of genome stability

“…CUL5 is expressed in normal renal collecting tubule cells 38 and the genomic locus of the CUL5 gene, chromosome 11q22-23, has recently been implicated as a risk locus for RCC in a genome-wide association study 39 .…”

“…CUL5 has previously been implicated to function as a tumor suppressor by regulating cellular proliferation 38 . CUL5 has been shown to be expressed in non-proliferating endothelial cells and downregulated during angiogenesis 41 .…”