Apigenin upregulation of CD26/DPPIV on colon epithelial cells requires inhibition of casein kinase 2

Abstract

Apigenin (4′,5,7-trihydroxyflavone) is a flavone present in the leafy herb parsley and in the dried flowers of chamomile, among other sources. Apigenin has a broad spectrum of activities that affect a variety of cellular processes, as we have reviewed (Lefort & Blay, 2013). These actions endow apigenin with the capacity to alter the relationship of cells with their surroundings and their interaction with key signaling molecules. We have reported that apigenin has the capacity to upregulate CD26/DPPIV (Lefort & Blay, 2011), a key enabler of such interactions with the external milieu (Cheng, Abdel-Ghany,

Does Oral Apigenin Have Real Potential for a Therapeutic Effect in the Context of Human Gastrointestinal and Other Cancers?

“…However, we have found that apigenin has a valuable and potentially synergistic advantage when given together with chemotherapeutics in certain cancer readouts (Lefort and Blay, 2011), meaning that its addition to existing combinations is inherently worthy of study. As we have illustrated in this review and elsewhere (Lefort and Blay, 2011;Lefort and Blay, 2013;Lefort et al, 2020), there is a great diversity of cellular responses that has been shown for apigenin in preclinical cancer models. It is therefore important that in early studies of efficacy in humans, all relevant cellular markers of progression are evaluated.…”

“…The flavone structure is a ready scaffold for further modification using medicinal chemistry (Singh et al, 2014). In our own work, we have shown that changes in hydroxylation or glycosylation have dramatic effects on the ability of apigenin to upregulate CD26, and thus potentially affect hallmarks of cancer (Lefort and Blay, 2011;Lefort et al, 2020). Therefore, using apigenin as a lead compound in drug development may be a valuable option for optimizing a small molecule to fully capture the beneficial effects that have been identified.…”

“…However, there is accumulating evidence that these varied interactions allow apigenin to modulate cellular regulatory pathways in ways that alter the behavior of both normal and neoplastic cells, particularly those of epithelial origin. This may depend on the state of lineage differentiation; we have shown that the ability of apigenin to upregulate the cell-surface regulator CD26/DPP4 on colon epithelial cells depends on the degree of differentiation in a series of carcinoma cell lines ( Lefort et al, 2020 ).…”

“…However, the ability of apigenin to regulate the function of cell-surface proteins is not directly exerted at the external face of the plasma membrane. For example, the ability of apigenin to upregulate DPP4 depends on inhibition of an intracellular kinase, casein kinase 2 (CK2) ( Lefort et al, 2020 ).…”

“…However more recently, we and others have drawn attention to the possibility that apigenin may have useful properties against cancer( Lefort and Blay, 2013 ; Shankar et al, 2017 ; Yan et al, 2017 ). In particular, we have noted that apigenin’s action at the cellular level is distinct from that of closely related flavones such as kaempferol and genistein( Lefort and Blay, 2011 ; Lefort et al, 2020 ).…”