Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis

Abstract

As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

“…These adoptive responses during hypoxia contribute to the aggressive behavior of many cancers and are largely mediated by HIF-1, the major transcription factor activated during hypoxia (Semenza, 2000(Semenza, , 2003Harris, 2002). Although HIF-1 usually participates in adoptive responses to hypoxia to promote tumor cell growth and survival, a possible role of HIF-1 in regulation of apoptosis has also been discussed (Carmeliet et al, 1998) …”

“…Hif-1a promotes cell death through an increase in p53 or other proapoptotic proteins such as Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3) or BNIP3L (NIX) (Carmeliet et al, 1998;Bruick, 2000;Guo et al, 2001;Sowter et al, 2001). Under most circumstances however, Hif-1a promotes survival of cancer or endothelial cells under hypoxic condition and also protects against apoptosis induced by serum deprivation or by anticancer agents (Alvarez-Tejado, 2001; Sasabe et al, 2005;Piret et al, 2004;Kim et al, 2004a, b;Zhang et al, 2004).…”

Increased expression of hypoxia-inducible factor 1α in type I and type II endometrial carcinomas

“…2 Hypoxia results in stabilization of HIF-1a, facilitating nuclear HIF-1a binding and restoration of oxygen homeostasis by inducing glycolysis and angiogenesis through upregulation of vascular endothelial growth factor (VEGF). 3 Experimental and clinical evidence suggest that the hypoxic fraction in solid tumors reduces sensitivity to conventional treatment modalities, influences growth and may increase malignant progression. 3,4 Importantly, hypoxia has been clinically demonstrated to predict an adverse treatment outcome in the radiotherapeutic management of cancer of the head and neck, uterine cervix and soft tissue sarcomas.…”

A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1

“…Therefore, we initially hypothesized that the ROSscavenging and iron-chelating potential of MCGA3 may play a role in the p21 induction by providing a hypoxic condition. Recent studies (Carmeliet et al, 1998;Abeysinghe et al, 2001;Goda et al, 2003) have shown that HIF-1a-involved p21 transcriptional activation without p53 transcriptional function. Our p21-promoter assays clearly reflect the p53-independent, Sp1-dependent transcriptional activation of p21 by MCGA3.…”

“…MCGA3 upregulates p21 as well as overcomes UVA-mediated early decrease of p21 Hypoxia not only induces angiogenesis and promotes cell growth and survival in cancer cells but also leads to growth arrest and apoptosis (Carmeliet et al, 1998;Goda et al, 2003;Greijer and van der Wall, 2004). Recently, hypoxia-mediated cell cycle arrest and induction of apoptosis has been shown to be regulated by p21 activation (Bossenmeyer-Pourie et al, 2002).…”