An approach to p32/gC1qR/HABP1: a multifunctional protein with an essential role in cancer

Abstract

P32/gC1qR/HABP1 is a doughnut-shaped acidic protein, highly conserved in eukaryote evolution and ubiquitous in the organism. Although its canonical subcellular localization is the mitochondria, p32 can also be found in the cytosol, nucleus, cytoplasmic membrane, and it can be secreted. Therefore, it is considered a multicompartmental protein. P32 can interact with many physiologically divergent ligands in each subcellular location and modulate their functions. The main ligands are C1q, hyaluronic acid, calreticulin, CD44, integrins, PKC, splicing factor ASF/SF2, and several microbial proteins. Among the functions in which p32 participates are mitochondrial metabolism and dynamics, apoptosis, splicing, immune response, inflammation, and modulates several cell signaling pathways. Notably, p32 is overexpressed in a significant number of epithelial tumors, where its expression level negatively correlates with patient survival. Several studies of gain and/or loss of function in cancer cells have demonstrated that p32 is a promoter of malignant hallmarks such as proliferation, cell survival, chemoresistance, angiogenesis, immunoregulation, migration, invasion, and metastasis. All of this strongly suggests that p32 is a potential diagnostic molecule and therapeutic target in cancer. Indeed, preclinical advances have been made in developing therapeutic strategies using p32 as a target. They include tumor homing peptides, monoclonal antibodies, an intracellular inhibitor, a p32 peptide vaccine, and p32 CAR T cells. These advances are promising and will allow soon to include p32 as part of targeted cancer therapies.

Keywords: A multifunctional protein; Biochemical properties; Ligands; Malignant promoter; Therapeutic cancer target; p32/gC1qR/HABP1/C1QBP.

Fig. 1

p32/gC1qR/HABP1 is a doughnut-shaped protein highly conserved in eukaryotic evolution. A Quaternary structure of p32 protein obtained from PDB based on the work published by Jiang et al. in 1999. p32 protein forms a doughnut-shaped quaternary structure integrated by three identical subunits. Each subunit is formed by an N-terminal alpha helix, a beta sheet formed by seven beta-chains and two C- terminal alfa helixes. B p32 protein is present and highly conserved in eukaryotic organisms from Caenorabditis elegans to humans. The figure shows the multiple alignments of C-terminal p32 sequences from model eukaryotic organisms (above), an evolutionary tree of p32 protein from the selected species (bottom left) and the percent of sequence identity between p32 protein of these model organisms respect to human p32 sequence (bottom right)

Fig. 2

Role of p32 in cell signaling. p32 exerts several functions in cell signaling at different levels as a ligand, a receptor, an intracellular regulator of receptors, regulator of modulator molecules as PKC, and a target effector downstream of signaling pathways. Some of the main signaling pathways involving p32 are: 1- extracellular p32 interacts with ɑ_vβ₃ integrin and promotes downstream activation of NF-κB, which translocates to the nucleus promoting the expression of MT1-MMP metalloproteinase, crucial for extracellular matrix degradation and invasion; 2-C1q activates multiple cell signaling pathways interacting with its receptors p32/gC1qR and calreticulin/cC1QR, which use different co-receptors such as DC-SIGN, CD44 and Integrins to transduce the signal; 3-p32 is recruited to caveolin lipid rafts after RTK activation, through its interaction with CD44 from the inside membrane monolayer enhancing RTKs autophosphorylation and promoting the activation of several signaling pathways downstream RTKs such as PI3K-Akt-mTOR-S6K and MAPK pathways; 4-Hialuronic Acid (HA) through its interaction with cell surface p32 can activate downstream PLCγ, inducing increased IP₃ levels, effect that is inhibited by anti-p32 monoclonal antibody; 5- PI3K-Akt signaling pathway is activated by p32 from the cell surface inducing a decrease in the levels of expression of IL-12 via a negative crosstalk with TLR4 receptor, effect that is inhibited by anti-p32 monoclonal antibody; 6-p32 interacts with different isoforms of PKC and modulates PKC-dependent cell signaling; 7-p32 is a target of ERK after mitogen activation, ERK induces translocation of p32 to the nucleus. Created with BioRender.com

Fig. 3

p32/gC1qR/HABP1 expression levels negatively correlates with patient survival in breast (p = 0.005240) (A), colorectal (p = 0.008218) (B), lung (p = 0.01794) (C) and skin (p = 0.003145) (D) cancer according with Kaplan–Meier graphics obtained from PrognoScan database