The dual role and therapeutic potential of high-mobility group box 1 in cancer

Abstract

High-mobility group box 1 (HMGB1) is an abundant protein in most eukaryocytes. It can bind to several receptors such as advanced glycation end products (RAGE) and Toll-like receptors (TLRs), in direct or indirect way. The biological effects of HMGB1 depend on its expression and subcellular location. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it possesses more complicated functions, including regulating cell proliferation, autophagy, inflammation and immunity. During tumor development, HMGB1 has been characterized as both a pro- and anti-tumoral protein by either promoting or suppressing tumor growth, proliferation, angiogenesis, invasion and metastasis. However, the current knowledge concerning the positive and negative effects of HMGB1 on tumor development is not explicit. Here, we evaluate the role of HMGB1 in tumor development and attempt to reconcile the dual effects of HMGB1 in carcinogenesis. Furthermore, we would like to present current strategies targeting against HMGB1, its receptor or release, which have shown potentially therapeutic value in cancer intervention.

Keywords: HMGB1; RAGE; TLRs; anticancer therapy; cancer.

Figure 1. Structure of the HMGB1 protein

(A) The 5 exons of human HMGB1 gene are indicated by boxes (hollow for translated regions and solid for un-translated regions). (B) The human HMGB1 protein has 215 amino acid residues and is composed of three domains: A box, B box and an acidic C-terminal tail. There are three redox-sensitive cysteine residues at positions 23, 45, and 106, which regulate HMGB1 function in response to oxidative stress. (C) The human HMGB1 is loosely and transiently associated with nucleosomes. In this location, HMGB1 is important for spatial segregation and nuclear homeostasis.

Figure 2. Release of the HMGB1 protein

There are two mechanisms of cells to release HMGB1 into the extracellular environment (passive release vs. active release). (A) HMGB1 is passively released into extracellular space from damaged cells or necrotic cells with leaky plasma membranes. Apoptotic cells that undergo secondary necrosis can also motivate late HMGB1 release. (B) HMGB1 can be actively released from activated cells such as inflammatory cells and immune cells. In this process, HMGB1 is acetylated, which prevents it from getting back to nucleus. Then the cytoplasmic HMGB1 is enveloped into secretory lysosomes, fuses with the cell membrane, and finally released into the environment.

Figure 3. Role of the HMGB1 protein in cancer progression

(A) In the extracellular space, HMGB1 signals through receptors (such as RAGE, TLRs, TIM3, and CXCR4), driving cell proliferation, invasion, metastasis, angiogenesis, apoptosis evasion, inflammation and immunity. The interaction between HMGB1 and CXCR4 is dependent on CXCL12. TLR9 is initially localized in the endoplasmic reticulum (ER), and redistributes to early endosomes upon stimulation with CpG-DNA via an HMGB1-dependent way. (B) HMGB1 present at the cell surface promotes cell migration and tumor-cell metastasis. (C) In the cytoplasm, HMGB1 regulates autophagy and promotes cell proliferation. (D) In the nucleus, HMGB1 acts as a DNA chaperone participating in DNA repair and transcription. HMGB1 can also interact with transcription factors and enhance their activities such as p53, p73, members of the Rel/NFκB family and RB. Nuclear HMGB1 enhances telomerase activity and modulates telomere homeostasis.

Figure 4. The therapeutic strategies targeting HMGB1 in cancer

(A) Inhibitors of HMGB1 protein. Extracellular HMGB1 can be blocked by administration of anti-HMGB1 antibodies (binds to HMGB1), HMGB1 box A (antagonizes the B box functional activity of HMGB1), and glycyrrhizin (binds to HMGB1). (B) Targeting receptors. Soluble RAGE (sRAGE) acts as a decoy to block HMGB1-RAGE signaling pathway. (C) Inhibition of HMGB1 secretion. The secretion of HMGB1 can be inhibited by ethyl pyruvate, glycyrrhizin and other agents (such as quercetin and nicotine).