Journal Article

Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF)

Ming-Tat Ling, Tracy C.M. Lau, Chun Zhou, Chee Wai Chua, Wai Kei Kwok, Qi Wang, Xianghong Wang and Yong-Chuan Wong

in Carcinogenesis

Volume 26, issue 10, pages 1668-1676
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi128
Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF)

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Androgen-independent metastatic prostate cancer is the main cause of cancer related death in men. One of the reasons for this is the lack of understanding of the molecular mechanisms leading to the metastatic progression of prostate cancer. In this study, we have demonstrated that overexpression of Id-1 (inhibitor of differentiation/DNA synthesis), a member of the helix–loop–helix family proteins, is a key factor in promoting angiogenesis through activation of the vascular endothelial growth factor (VEGF) in prostate cancer cells. Using prostate cancer cells ectopically transfected with the Id-1 gene, we found that upregulation of Id-1 induced VEGF secretion through activation of the VEGF gene transcription. Downregulation of Id-1, however, led to the suppression of VEGF secretion and its gene promoter activity. The association between Id-1 and VEGF was also confirmed on human xenografts by immunohistochemical staining. In addition, the growth medium generated by the Id-1 expressing cells was able to promote morphological changes as well as capillary tube formation in human umbilical vein endothelial cells (HUVECs) at similar degrees to the recombinant human VEGF. Furthermore, inhibition of VEGF function by the treatment with an Flk-1 inhibitor, SU1498, or with the VEGF neutralizing antibody resulted in the reverse of the angiogenic effect on HUVECs. Our results suggest that overexpression of Id-1 in prostate cancer cells may provide an autocrine signal to promote angiogenesis through the activation of VEGF. Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through the suppression of angiogenesis.

Keywords: BMP, bone morphogenic protein; BrdU, bromodeoxyuridine; DAPI, 4′,6-diamidino-2-phenylindole; EGM2, Endothelial Cell Medium-2; ELISA, enzyme-linked immunosorbent assay; FCS, fetal calf serum; HUVECs, human umbilical vein endothelial cells; Id-1, inhibitor of differentiation/DNA synthesis; MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor

Journal Article.  6144 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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