“… 86 , 87 The hydrophobic effect of EZH2 myristoylation promotes droplets formation to separate from the surrounding solution, which is conducive to the interaction with STAT3 and downstream growth regulation. 88 N-Myristoylation Predictive Tools are developed based on the PROSITE motif in substrate proteins 89 ( http://mendel.imp.univie.ac.at/myristate/ ), the difference between myristoylated and non-myristoylated proteins 90 ( http://www.expasy.org/tools/myristoylator/myristoylator.html ) and pattern scanning 91 ( http://www.isv.cnrs-gif.fr/terminator3/index.html ). Fig.…”
Section: Lipid-related Protein Modificationmentioning
More and more in-depth studies have revealed that the occurrence and development of tumors depend on gene mutation and tumor heterogeneity. The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment (TME) heterogeneity. This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network. TME has resulted in novel therapeutic interventions as a place beyond tumor beds. The malignant cancer cells, tumor infiltrate immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells, and the released factors including intracellular metabolites, hormonal signals and inflammatory mediators all contribute actively to cancer progression. Protein post-translational modification (PTM) is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis. Advances in quantitative transcriptomics, proteomics, and nuclease-based gene editing are now paving the global ways for exploring PTMs. In this review, we focus on recent developments in the PTM area and speculate on their importance as a critical functional readout for the regulation of TME. A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.
“… 86 , 87 The hydrophobic effect of EZH2 myristoylation promotes droplets formation to separate from the surrounding solution, which is conducive to the interaction with STAT3 and downstream growth regulation. 88 N-Myristoylation Predictive Tools are developed based on the PROSITE motif in substrate proteins 89 ( http://mendel.imp.univie.ac.at/myristate/ ), the difference between myristoylated and non-myristoylated proteins 90 ( http://www.expasy.org/tools/myristoylator/myristoylator.html ) and pattern scanning 91 ( http://www.isv.cnrs-gif.fr/terminator3/index.html ). Fig.…”
Section: Lipid-related Protein Modificationmentioning
More and more in-depth studies have revealed that the occurrence and development of tumors depend on gene mutation and tumor heterogeneity. The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment (TME) heterogeneity. This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network. TME has resulted in novel therapeutic interventions as a place beyond tumor beds. The malignant cancer cells, tumor infiltrate immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells, and the released factors including intracellular metabolites, hormonal signals and inflammatory mediators all contribute actively to cancer progression. Protein post-translational modification (PTM) is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis. Advances in quantitative transcriptomics, proteomics, and nuclease-based gene editing are now paving the global ways for exploring PTMs. In this review, we focus on recent developments in the PTM area and speculate on their importance as a critical functional readout for the regulation of TME. A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.
“…To reduce the cytotoxicity of CS-piscidin and increase its specificity, we modified it by adding the tumor-targeting peptide Cyclo-RGDfk to the C-terminus of CS-piscidin, resulting in CS-RGD. We also added a myristate group to the N-terminus of the CS-RGD peptide to enhance tumor targeting, based on previous reports indicating that cancer cells require myristic acid for cell membrane formation and energy production [ 23 , 24 ]. As shown in Fig.…”
Ovarian cancer (OC) is a highly lethal gynecological malignancy, often diagnosed at advanced stages with limited treatment options. Here, we demonstrate that the antimicrobial peptide CS-piscidin significantly inhibits OC cell proliferation, colony formation, and induces cell death. Mechanistically, CS-piscidin causes cell necrosis by compromising the cell membrane. Furthermore, CS-piscidin can activate Receptor-interacting protein kinase 1 (RIPK1) and induce cell apoptosis by cleavage of PARP. To improve tumor targeting ability, we modified CS-piscidin by adding a short cyclic peptide, cyclo-RGDfk, to the C-terminus (CS-RGD) and a myristate to the N-terminus (Myr-CS-RGD). Our results show that while CS-RGD exhibits stronger anti-cancer activity than CS-piscidin, it also causes increased cytotoxicity. In contrast, Myr-CS-RGD significantly improves drug specificity by reducing CS-RGD toxicity in normal cells while retaining comparable antitumor activity by increasing peptide stability. In a syngeneic mouse tumor model, Myr-CS-RGD demonstrated superior anti-tumor activity compared to CS-piscidin and CS-RGD. Our findings suggest that CS-piscidin can suppress ovarian cancer via multiple cell death forms and that myristoylation modification is a promising strategy to enhance anti-cancer peptide performance.
Graphical Abstract
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