Biochemical pharmacology of adenylyl cyclases in cancer

Abstract

Globally, despite extensive research and pharmacological advancement, cancer remains one of the most common causes of mortality. Understanding the signaling pathways involved in cancer progression is essential for the discovery of new drug targets. The adenylyl cyclase (AC) superfamily comprises glycoproteins that regulate intracellular signaling and convert ATP into cyclic AMP, an important second messenger. The present review highlights the involvement of ACs in cancer progression and suppression, broken down for each specific mammalian AC isoform. The precise mechanisms by which ACs contribute to cancer cell proliferation and invasion are not well understood and are variable among cancer types; however, AC overactivation, along with that of downstream regulators, presents a potential target for novel anticancer therapies. The expression patterns of ACs in numerous cancers are discussed. In addition, we highlight inhibitors of AC-related signaling that are currently under investigation, with a focus on possible anti-cancer strategies. Recent discoveries with small molecules regarding more direct modulation AC activity are also discussed in detail. A more comprehensive understanding of different components in AC-related signaling could potentially lead to the development of novel therapeutic strategies for personalized oncology and might enhance the efficacy of chemoimmunotherapy in the treatment of various cancers.

Keywords: Adenylyl Cyclase; Cancer; G protein; GPCR; Hallmarks of Cancer; cAMP signaling.

Figure 1.

Regulation and physiological signaling of transmembrane adenylyl cyclases (ACs). Traditionally, ACs are activated and inhibited via Gα_s- and Gα_i-linked G protein-coupled receptors (GPCRs), respectively. Activation of AC stimulates the production of cyclic adenosine monophosphate (cAMP) from the cellular energy source, ATP. The accumulation of cAMP is balanced by cAMP-dependent phosphodiesterases (PDEs) that terminate signaling though enzymatic degradation of cAMP. The effectors of cAMP include protein kinase A (PKA), exchange protein activated by cAMP (EPAC), Popeye Domain Containing (POPDC) proteins, and cyclic nucleotide-gated channels (CNGCs). A kinase anchoring proteins (AKAPs) are scaffolding proteins that are involved in compartmentalization and regulation of AC signaling involving PKA. Figure adapted from [7] with permission.

Figure 2.

Groups of AC isoforms. The transmembrane ACs divided in the four groups based on key regulatory features. Group 1 ACs (blue) are stimulated by Ca²⁺/CaM. Group 2 ACs (green) are conditionally activated by Gβγ and group 3 ACs (red) are inhibited by Ca²⁺. AC9 is sole member of group 4 (orange) and is only known to be directly modulated by Gα_s. There are additional unique regulatory properties that include isoform specific regulation by protein kinase A (PKA) and C (PKC). Solid lines indicate direct regulation with green for activation and red for inhibition. The dashed lines indicate conditional regulatory effects. NO, nitric oxide. Figure adapted from [7] with permission.

Figure 3.

Physiological expression patterns of ACs (left) and cancer-specific expression (right). Tissues and cells express multiple AC isoforms from within and across each AC group. Group 1 is shown in blue, group 2 in green, group 3 in red, and group 4 is depicted in orange. In the right panel, numbers in brackets indicate the relevant reference. Figure adapted from [7] with permission.

Figure 4.

Heat map of AC isoform expression in different cancers relative to non-cancer control tissues. Bulk gene expression for the indicated cancers and paired adjacent normal tissues, from the Cancer Genome Atlas, was plotted in GEPIA [175] using the multiple gene analysis/multiple gene comparison function. Gene expression values were plotted as log₂([transcripts per million] + 1). The fold change of tumor vs. normal was calculated for each AC and cancer type. Because the lowest non-zero values in the data set were 0.1, any values for which the reported expression was 0.0 were set to 0.09. Cells are colored red if expression in the tumor samples was increased over the paired normal samples with cutoff of ≥ 1.5 fold; cells are colored blue if expression in the tumor samples was decreased over the paired normal samples with a cutoff of ≤ 0.67 fold. A similar analysis was shown in [8].

Figure 5.

Representative transmembrane AC modulators separated by class. Class 1 modulators include nucleotide analogs. Class 2 modulators represent the non-competitive/uncompetitive P-site inhibitors. Class 3 represent the forskolin-based modulators. Class 4 represent modulators interacting at other potential allosteric sites or scaffolds with limited mechanistic information.