Hypoxia regulation of expression and angiogenic effects of vasoactive intestinal peptide (VIP) and VIP receptors in LNCaP prostate cancer cells

Vascular endothelial growth factor (VEGF) is a main factor promoting neovascularization (angiogenesis) of solid tumours as prostate carcinoma. Hypoxia stimulates VEGF gene expression by activating the hypoxia-inducible factor-1 (HIF-1α). In the present study, the hypoxia-mimicking agent Ni2+ induced vasoactive intestinal peptide (VIP) expression at both mRNA and peptide levels but it did not modify the expression of VIP receptors (VPAC1, VPAC2 and PAC1 receptors) in androgen-dependent human LNCaP prostate cancer cells. VIP increased the mRNA levels of VPAC1 and PAC1 receptors whereas it decreased VPAC2 receptor mRNA level. These features support that hypoxia up-regulation of VIP gene expression in prostatic carcinoma may lead to VIP regulation of the expression of its receptors by means of autocrine/paracrine mechanisms. Either VIP or hypoxia mimetics with Ni2+ increased VEGF expression whereas both conditions together resulted in an additive response. It suggests two independent mechanisms for the observed pro-angiogenic activities of VIP and hypoxia. VIP did not stimulate HIF-1α mRNA expression but increased the translocation of HIF-1α from the cytosolic compartment to the cell nucleus. Moreover, VIP was unable to modify the expression of the HIF-1α inhibitor FIH-1 discarding the possibility of an indirect effect of VIP on HIF-1 transactivation.