Targeting HIF-1 for cancer therapy

Abstract

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

“…Finally, the inhibition of HIF1a expression markedly suppressed synthesis of vascular endothelial growth factor (VEGF) as determined in EIA with the ALK þ TCL cell culture supernatants (Figure 4d). Our findings indicate that ALK þ TCL cells express HIF1a, an important oncogenic protein found in other types of malignancy to be involved in tumor angiogenesis, growth, invasive properties, metastasis formation and resistance to therapy (Semenza, 2003;Bertout et al, 2008). Although the expression of HIF1a mRNA is persistent and independent of cell oxygenation status, HIF1a is strongly expressed in response to hypoxia.…”

“…Indeed, STAT3 has been recently shown to induce HIF1a transcription in v-Srctransfected murine 3T3 fibroblasts and in a human melanoma cell line (Niu et al, 2008). Although the phosphoinositide 3-kinase/AKT and MEK/ERK pathways have also been implicated in HIF1a synthesis, they seem to impact primarily, if not exclusively, the translation, rather than the transcription of HIF1a, by activating the mTORC1 complex - (Semenza, 2003). It is well established that HIF1a promotes carcinogenesis by various mechanisms, including the enhancement of tumor angiogenesis, invasion, metastasis and resistance to therapy (Semenza, 2003;Bertout et al, 2008).…”

“…Hypoxia-inducible factor 1 (HIF1) has an important role in carcinogenesis by fostering tumor angiogenesis, invasive properties, metastasis formation and resistance to therapy (Semenza, 2003;Bertout et al, 2008). This heterodimeric transcription factor is composed of a-and b-subunits, with expression of the former being tightly controlled by the degree of cell oxygenation.…”

“…In contrast to the regulation of protein degradation, the mechanisms inducing HIF1a expression are less known. Several growth factor and cytokine receptors such as epidermal growth factor receptor and interleukin (IL)-6R that frequently have a key role in carcinogenesis have been implicated in the regulation of HIF1a expression mainly by affecting protein synthesis (Semenza, 2003).…”

Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?

“…1). HIF-1 α and HIF-2 α induction would lead to the modulation of >200 genes important for inducing tumor angiogenesis, cancer cell growth/survival, and energy metabolism; mediating resistance [43, 44]. In addition to mediating reactive resistance, HIF-1 α and HIF-2 α also mediate primary resistance due to their induction through dysregulated growth signaling by inflammatory mediators, growth factors, and mutations in cancer genes [45–54].…”