Background: Mucin1 (MUC1) is a highly glycosylated transmembrane protein that has gained attention because of its overexpression in various cancers. However, MUC1-targeted therapeutic antibodies have not yet been approved for cancer therapy. MUC1 is cleaved to two subunits, MUC1-N and MCU1-C. MUC1-N is released from the cell surface, making MUC1-C a more reasonable target for cancer therapy. Therefore, we produced a monoclonal antibody (anti-hMUC1) specific to the extracellular region of MUC1-C and evaluated its effects in vitro and in vivo.

The ankyrin repeat and suppressor of cytokine signalling (SOCS) box proteins (Asbs) are a large protein family implicated in diverse biological processes including regulation of proliferation and differentiation. The SOCS box of Asb proteins is important in a ubiquitination-mediated proteolysis pathway. Here, we aimed to evaluate expression and function of human Asb-9 (ASB9).

Byoung Kwon Park, Dongbum Kim, Sangkyu Park, Sony Maharjan, Jinsoo Kim, Jun-Kyu Choi, Madhav Akauliya, Younghee Lee,* and Hyung-Joo Kwon,*. Biomolecules & Therapeutics 2021;29:273-81. https://doi.org/10.4062/biomolther.2020.226

Background: The screening of peptide-based epitopes has been studied extensively for the purpose of developing therapeutic antibodies and prophylactic vaccines that can be potentially useful for treating cancer and infectious diseases such as influenza virus, malaria, hepatitis B, and HIV. To improve the efficacy of antibody production by epitope-based immunization, researchers evaluated liposomes as a means of delivering vaccines; they also formulated adjuvants such as flagella and CpG-DNA to enhance the magnitude of immune responses. Here, we provide a potent method for peptide-based epitope screening and antibody production without conventional carriers. Results: We present that a particular form of natural phosphodiester bond CpG-DNA encapsulated in a specific liposome complex (Lipoplex(O)) induces potent immunomodulatory activity in humans as well as in mice. Additionally, Lipoplex(O) enhances the production of IgG2a specific to antigenic protein in mice. Most importantly, immunization of mice with several peptides co-encapsulated with Lipoplex(O) without carriers significantly induces each peptide-specific IgG2a production in a TLR9-dependent manner. A peptide-specific monoclonal antibody produced against hepatocellular carcinoma-associated antigen has functional effects on the cancer cells. Conclusions: Our overall results show that Lipoplex(O) is a potent adjuvant and that complexes of peptide and Lipoplex(O) are extremely useful for B cell epitope screening and antibody production without carriers. Therefore, our strategy may be promptly used for the development of therapeutic antibodies by rapid screening of potent B cell epitopes.

Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer

Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90α and HSP90β), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N-acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors.