Biology subjects

Kim, S.-A.

Publications and source records attributed to Kim, S.-A..

3 recordsLinked to original sources

bioRxiv2024

Loss of p21-activated kinase 4 (PAK4) suppresses pancreatic tumor progression and metastasis through regulating E-cadherin

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis with early and frequent metastasis. While p21-activated kinase 4 (PAK4) has been implicated in cell migration, and invasion, the molecular mechanisms in PDAC remain unknown. In this study, we found that PAK4 overexpression was correlated with poor survival in PDAC patients through analysis of TCGA data. PAK4-amplified PDAC cells showed enhanced mobility in contrast with wild-type. PAK4 knockdown in PAK4 amplified cells inhibited cell migration, invasion, and displacement by increased and stabilized E-cadherin, which was attributed to decreased activity of Cdc42. PAK4 knock-in in PAK4 wild-type models enhanced cell migration, invasion, and displacement by reduced E-cadherin through elevated Cdc42 activity. PAK4 bounded to E-cadherin, Cdc42, and p120ctn in immunoprecipitation. In confocal imaging, the colocalization of PAK4, E-cadherin, p120ctn, and Cdc42 was also identified. In an orthotopic PDAC mouse model, PAK4 knockdown decreased primary tumor size and occurrence of malignant ascites by activation of E-cadherin. Notably, in patients tissue specimens, inverse correlation on expression of PAK4 and E-cadherin were also shown. In conclusion, our study highlights that PAK4 promotes invasive and metastatic behavior by regulating E-cadherin in PDAC. PAK4 could be a potential therapeutic target for PDAC patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/594599v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1755a23org.highwire.dtl.DTLVardef@170b2a1org.highwire.dtl.DTLVardef@1df96edorg.highwire.dtl.DTLVardef@2dc46b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Improved vascularized lymph node transfer by periodic injection of hyaluronidase in a rodent model

BackgroundVascularized lymph node transfer (VLNT) is an advanced surgical approach for secondary lymphedema (SLE) treatment, but tissue fibrosis around the lymph node flap (VLNF) inhibiting lymphangiogenesis is the biggest challenge undermining its therapeutic efficacy. Hyaluronidase (HLD), which is an enzyme that breaks down hyaluronic acid, may have the efficacy of reducing fibrosis and increasing the chance of lymphangiogenesis in the injury site. Materials and methods52 Sprague-Dawley rats with VLNF were divided into a group injected periodically with HLD and a control group and followed up. A follow-up study was performed for 13 weeks starting 1 week after model formation was examined. The limb volume and dermal backflow pattern were observed to evaluate the degree of lymphedema. The real-time ICG fluorescence intensity changes were measured to evaluate the degree of lymphatic drainage to the flap. Lastly, the number of regenerative lymphatic vessels and the degree of fibrosis were investigated. ResultsIn the group injected with HLD periodically (VLNF+HLD group), swelling reduction and dermal backflow pattern recovery occurred rapidly in the 3rd week of follow-up compared to the only VLNF group. Moreover, the efficiency of lymphatic drainage into the flap was also improved in the VLNF+HLD group. They significantly had more newly formed lymphatic vessels along with a decrease in collagen fiber decomposition in the tissue around the VLNF by up to 26%. ConclusionThese encouraging results pave the way for developing a combination strategy for SLE treatment involving HLD and VLNT. Furthermore, this finding may guide future research on the development of new drugs that could enhance the efficacy of VLNT surgery for SLE patients. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/586511v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12b4c7forg.highwire.dtl.DTLVardef@1ab4538org.highwire.dtl.DTLVardef@14d93adorg.highwire.dtl.DTLVardef@1a6b87_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as novel inhibitor for ELF3-MED23 Interaction

HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success, however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab. In this study, we synthesized a total of 26 compounds consisting of 10 chalcones, 7 pyrazoline acetyl, and 9 pyrazoline propionyl derivatives, and evaluated their biological activity as potential ELF3-MED23 PPI inhibitors. Upon systematic analysis, candidate compound 10 was selected due to its potency in downregulating reporter gene activity of ERBB2 promoter confirmed by SEAP activity and its effect on HER2 protein and mRNA levels. Compound 10 effectively disrupted the binding interface between the ELF3 TAD domain and the 391-582 amino acid region of MED23, resulting in successful inhibition of the ELF3-MED23 PPI. This intervention led to a substantial reduction in HER2 levels and its downstream signals in the HER2-positive gastric cancer cell line. Subsequently, compound 10 induced significant apoptosis and anti-proliferative effects, demonstrating superior in vitro and in vivo anticancer activity overall. We found that the anticancer activity of compound 10 was not only restricted to trastuzumab-sensitive cases, but was also valid for trastuzumab-refractory clones. This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

pharmacology and toxicology↗