ABSTRACT
The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.
Subject(s)
Hyperlipoproteinemia Type II , Humans , Spain , Hyperlipoproteinemia Type II/genetics , Mutation , Receptors, LDL/genetics , HeterozygoteABSTRACT
Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal. Herein, we report the antitumor effects of CM728, a novel quinone-fused oxazepine, against this malignancy. CM728 potently inhibited TNBC cell viability and decreased the growth of MDA-MB-231-induced orthotopic tumors. Furthermore, CM728 exerted a strong synergistic antiproliferative effect with docetaxel in vitro and this combination was more effective than the individual treatments in vivo. Chemical proteomic approaches revealed that CM728 bound to peroxiredoxin-1 (Prdx1), thereby inducing its oxidation. Molecular docking corroborated these findings. CM728 induced oxidative stress and a multi-signal response, including JNK/p38 MAPK activation and STAT3 inhibition. Interestingly, Prdx1 downregulation mimicked these effects. Finally, CM728 led to DNA damage, cell cycle blockage at the S and G2/M phases, and the activation of caspase-dependent apoptosis. Taken together, our results identify a novel compound with antitumoral properties against TNBC. In addition, we describe the mechanism of action of this drug and provide a rationale for the use of Prdx1 inhibitors, such as CM728, alone or in combination with other drugs, for the treatment of TNBC.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Apoptosis , Cell Line, Tumor , Cell Proliferation , Docetaxel/pharmacology , Molecular Docking Simulation , Proteomics , Triple Negative Breast Neoplasms/genetics , Xenograft Model Antitumor AssaysABSTRACT
In this study, a series of new 4,4'-diaminotriphenylmethanes was efficiently synthesized from aromatic aldehydes and 2,5-dimethoxybenzenamine under microwave irradiation in the presence of Sc(OTf)3 as a catalyst. Antiproliferative activity was assessed by using the MCF-7 estrogen receptor (ER)-positive breast cancer cell line, and antagonist/agonist transcriptional activities were determined. Docking studies and competition studies of triphenylmethanes and radiolabeled estradiol determined that these compounds do not bind the ER, indicating that triphenylmethane-induced changes in proliferative and transcriptional activities differ from conventional mechanisms of action triggered by other selective ER modulators.
Subject(s)
Methane/chemistry , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemical synthesis , Binding Sites , Cell Proliferation/drug effects , Female , Humans , MCF-7 Cells , Methane/chemical synthesis , Methane/toxicity , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Receptors, Estrogen/chemistry , Receptors, Estrogen/genetics , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/toxicity , Transcriptional Activation/drug effectsABSTRACT
GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway. Therefore, the interactions of estrogens with GH actions in liver are biologically and clinically relevant because disruption of GH signaling may cause alterations of its endocrine, metabolic, and gender differentiated functions and it could be linked to dramatic impact in liver physiology during development as well as in adulthood. Finally, the interplay of estrogens with GH is relevant because physiological roles these hormones have in human, and the widespread exposition of estrogen or estrogen-related compounds in human. This review highlights the importance of these hormones in liver physiology as well as how estrogens modulate GH actions in liver which will help to improve the clinical use of these hormones.
