Bacterial cupredoxin azurin hijacks cellular signaling networks: Protein-protein interactions and cancer therapy

Abstract

Azurin secreted by Pseudomonas aeruginosa is an anticancer bacteriocin, which preferentially enters human cancer cells and induces apoptosis or growth inhibition. It turns out that azurin is a multi-target anticancer agent interfering in the p53 signaling pathway and the non-receptor tyrosine kinases signaling pathway. This suggests that azurin exerts its anticancer activity by interacting with multiple targets and interfering in multiple steps in disease progression. Therefore, azurin could overcome resistance to therapy. Besides azurin, putative bacteriocins that possess functional properties similar to those of azurin have been identified in more bacteria species. A systematic investigation on the anticancer mechanisms of azurin and the azurin-like bacteriocins will provide more and better options in cancer therapy. In this review, we summarize how azurin and the derived peptides hijack key cellular regulators or cell surface receptors to remodel the cellular signaling networks. In particular, we highlight the necessity of determining the structure of azurin/p53 complex and investigating the influence of post-translational modifications on interactions between azurin and p53. Therapeutic applications of azurin and derived peptides are also discussed.

Keywords: Anticancer drugs; bacterial proteins; non-receptor tyrosine kinases; p53; tumor suppression.

Figure 1

Mechanisms of azurin to induce apoptosis and growth inhibition of human cancer cells. Azurin enters cancer cells and forms complexes with p53, inhibiting ubiquitin‐mediated degradation of p53 and increasing its level. The stabilized p53 travels back into the nucleus and transcriptionally induces proapoptotic genes such as Bax and Noxa or cell cycle inhibitors such as p21 and p27. Azurin also binds to the cell surface receptors, including VEGFR‐2, integrin β₁, P‐cadherin, and EphB2, interfering in their signal transduction pathways that converge to NRTKs.

Figure 2

Interactions between azurin and p53. p53 FL consists of a TAD, a proline‐rich region, a DBD, a TET domain, and an extreme C terminus. Interactions between specific p53 domain and azurin are shown by the black lines, where the binding affinities obtained and the experimental techniques used are indicated.

Figure 3

Illustrative structures of p53 bound to different partners. The first row: the p53 TAD binds to the Taz2 domain of p300 (2K8F), the PH domain of TFIIH subunit p62 (2RUK), MDM2 (1YCR), and the nuclear coactivator‐binding domain of CBP (2L14). The second row: the p53 DBD binds to the brca1 CTD of 53BP1 (1KZY), DNA (1TUP), Bcl‐xL (2MEJ), and oncoprotein SV40 large T‐antigen (2H1L). The third row: the p53 CT binds to the bromodomain of CBP (1JSP), the tandem Tudor domain of 53BP1 (2MWO), and 14‐3‐3σ (3LW1). The p53 fragments are shown in orange and the interacting partners are shown in gray.