👤 Lie-Fen Shyur

Drug resistance is a major challenge in colorectal cancer (CRC) treatment. Overcoming drug resistance and improving therapeutic outcomes are crucial issues for patients with drug-resistant CRC. Crassocephalum rabens (Benth.) S. Moore (CR) is an edible plant and a folk medicine. Its galactolipids have anti-inflammatory and antitumor potential. This study explored the pharmacological mechanism and therapeutic efficacy of galactolipids isolated from CR (designated CRA) for treating drug-resistant CRC in vitro and in vivo. The antitumor activity and molecular mechanisms of CRA were investigated using cytotoxicity, reactive oxygen species (ROS) production, RNA sequencing, quantitative PCR (qPCR), Western blotting, and LPA concentration assays. Virtual molecular docking was conducted to identify CRA's action site on the target protein. The therapeutic effectiveness of CRA was evaluated using HT-29 xenograft mice. CRA induced ROS-mediated cytotoxicity by inhibiting the expression of interferon-α-induced protein 6 (IFI6). IFI6 suppression by CRA led to ROS accumulation and oxidative DNA damage, ultimately resulting in cell death. CRA antagonistically targeted lysophosphatidic acid receptors (LPAR), specifically LPAR2, and blocked their downstream signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/p38, PLC/PKC, Rho/PKA, and NF-κB, which inhibited cell survival. Furthermore, CRA also inhibited the intracellular synthesis of LPA. In HT-29 tumor-bearing mice, CRA significantly reduced tumor growth. The antitumor activity of CRA, through inhibiting LPAR2 expression and inducing IFI6-mediated oxidative stress, was also observed in tumors. CR galactolipids directly targeted LPAR2, inhibited the LPAR2 signaling pathways, and induced IFI6-mediated ROS accumulation to combat drug-resistant CRC. Show less

Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases. Show less