Specific Inhibition of HIF Activity: Can Peptides Lead the Way?

Abstract

Reduced oxygen availability (hypoxia) is a characteristic of many disorders including cancer. Central components of the systemic and cellular response to hypoxia are the Hypoxia Inducible Factors (HIFs), a small family of heterodimeric transcription factors that directly or indirectly regulate the expression of hundreds of genes, the products of which mediate adaptive changes in processes that include metabolism, erythropoiesis, and angiogenesis. The overexpression of HIFs has been linked to the pathogenesis and progression of cancer. Moreover, evidence from cellular and animal models have convincingly shown that targeting HIFs represents a valid approach to treat hypoxia-related disorders. However, targeting transcription factors with small molecules is a very demanding task and development of HIF inhibitors with specificity and therapeutic potential has largely remained an unattainable challenge. Another promising approach to inhibit HIFs is to use peptides modelled after HIF subunit domains known to be involved in protein–protein interactions that are critical for HIF function. Introduction of these peptides into cells can inhibit, through competition, the activity of endogenous HIFs in a sequence and, therefore also isoform, specific manner. This review summarizes the involvement of HIFs in cancer and the approaches for targeting them, with a special focus on the development of peptide HIF inhibitors and their prospects as highly-specific pharmacological agents.

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

“…Below, we briefly report the main aspects of the inhibition strategy and examples of chemical agents used. For a more detailed discussion about drugs, targets, and mechanisms, more specific reviews should be consulted [ 121 , 122 , 123 ].…”

Transcriptomic Analysis Reveals Differential Expression of Genes between Lung Capillary and Post Capillary Venules in Abdominal Sepsis

“…Targeting transcription factors using small molecules is known to be difficult because of complicated protein–protein and/or protein-DNA interactions. Interestingly, recent progress in peptide-based drug targets has been shown to accomplish such challenges to some extent [ 54 , 55 ]. However, it should be noted that targeting a transcription factor that regulates many biological processes may simultaneously disrupt other critical physiological responses, and further research is needed before clinical use.…”

Vitamin D and Hypoxia: Points of Interplay in Cancer

“…Extensive investigation during the past decades has shown that HIF-1α and HIF-2α are significantly controlled by diverse intracellular signaling pathways not directly affected by oxygen levels. Most of these pathways culminate in HIF-1α/HIF-2α phosphorylation, which regulates their stability, localization, protein interactions, and subsequently activity ( Figure 4 ) [ 25 , 78 ].…”

“…As such, HIFs are often correlated with resistance to conventional therapy options and negative patient prognosis, much like vitamin D deficiency. Given the essential impact of HIFs and hypoxia in cancer, it is no wonder that HIFs are meaningful targets for agents with anticancer abilities, including naturally occurring compounds [ 24 , 25 , 26 ]. Furthermore, apart from HIF induction, lack of oxygen contributes to dysregulated signaling cascades [ 27 ] and compromised catalytic activity of enzymes such as the monooxygenase family members that use the molecular oxygen as a substrate and are heavily implicated in vitamin D converting reactions [ 28 ].…”