Snail Mucus Induces Cytotoxicity and Chemosensitivity of Triple-Negative Breast Cancer Cells via Activation of Fas Signaling Pathway

BackgroundTriple-negative breast cancers (TNBCs) patients showed poor survival outcomes due to chemoresistance, and the development of new therapeutic strategies is urgently needed. The development of cancer is mainly related to chronic inflammation. Therefore, the pharmacological reduction of inflammation by natural extract components may promote anti-cancer activity and increase chemosensitivity. Snail mucus has been reported to possess the ability against inflammation, a process closely related to tumorigenesis, suggesting a potential anti-cancer function. The direct cytotoxic activity of snail mucus in cancer cells was investigated in this study.Methods The effect of snail mucus on cell viability in breast cancer cells and normal epithelial cells were measured by MTT and IncuCyte Live-cell analysis. The active fractions of snail mucus were isolation by performing MPLC and the anti-cancer ingredients were identified by NMR spectrometer analysis.Results Snail mucus significantly decreased the proliferation and viability of TNBC cells with relatively lower cytotoxicity to normal breast epithelial cells and enhanced their response to chemotherapy. Mechanistically, snail mucus induces an extrinsic apoptotic pathway through activation of Fas signaling by suppressing nucleolin. Two possible peptide fractions have also been identified as the anti-cancer ingredients of the snail mucus.ConclusionsIn summary, snail mucus can induce programmed cell death via the extrinsic apoptotic pathway and might have therapeutic potential with chemo-sensitizing effect for TNBCs.

KCC2 is required for the survival of mature neurons but not for their development

ABSTRACTThe K+/Cl– co-transporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl− levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors GABAARs. In accordance with this, compromised KCC2 activity results in seizures but whether such deficits directly contribute to the subsequent changes in neuronal viability that lead to epileptogenesis, remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression resulted in the rapid activation of the extrinsic apoptotic pathway, in mature hippocampal neurons. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization or dendritic structure. However ablating KCC2 expression in immature neurons was sufficient to prevent the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to loss of KCC2 function. In contrast KCC2 appears to play a minimal role in mediating neuronal development or architecture.

Role of Extrinsic Apoptotic Signaling Pathway during Definitive Erythropoiesis in Normal Patients and in Patients with β-Thalassemia

Apoptosis is a process of programmed cell death which has an important role in tissue homeostasis and in the control of organism development. Here, we focus on information concerning the role of the extrinsic apoptotic pathway in the control of human erythropoiesis. We discuss the role of tumor necrosis factor α (TNFα), tumor necrosis factor ligand superfamily member 6 (FasL), tumor necrosis factor-related apoptosis-inducing (TRAIL) and caspases in normal erythroid maturation. We also attempt to initiate a discussion on the observations that mature erythrocytes contain most components of the receptor-dependent apoptotic pathway. Finally, we point to the role of the extrinsic apoptotic pathway in ineffective erythropoiesis of different types of β-thalassemia.

Human Embryonic Stem Cells Acquire Responsiveness to TRAIL upon Exposure to Cisplatin

Tumor necrosis factor-related apoptosis-inducing ligand—TRAIL—is a protein operating as a ligand capable of inducing apoptosis particularly in cancerously transformed cells, while normal healthy cells are typically nonresponsive. We have previously demonstrated that pluripotent human embryonic stem cells (hESC) are also refractory to TRAIL, even though they express all canonical components of the death receptor-induced apoptosis pathway. In this study, we have examined a capacity of DNA damage to provoke sensitivity of hESC to TRAIL. The extent of DNA damage, behavior of molecules involved in apoptosis, and response of hESC to TRAIL were investigated. The exposure of hESC to 1 μM and 2 μM concentrations of cisplatin have led to the formation of 53BP1 and γH2AX foci, indicating the presence of double-strand breaks in DNA, without affecting the expression of proteins contributing to mitochondrial membrane integrity. Interestingly, cisplatin upregulated critical components of the extrinsic apoptotic pathway—initiator caspase 8, effector caspase 3, and the cell death receptors. The observed increase of expression of the extrinsic apoptotic pathway components was sufficient to sensitize hESC to TRAIL-induced apoptosis; immense cell dying accompanied by enhanced PARP cleavage, processing of caspase 8, and full activation of caspase 3 were all observed after the treatment combining cisplatin and TRAIL. Finally, we have demonstrated the central role of caspase 8 in this process, since its downregulation abrogated the sensitizing effect of cisplatin.