Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy

Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small‐molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL‐2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3‐ or SMAC‐mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3‐mimetics indicate that the antiapoptotic BCL‐2 protein MCL‐1 and its antagonist NOXA are particularly important regulators of BCL‐2 family signaling, while SMAC‐mimetic studies show that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although most solid tumors, including melanoma, are insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF‐inhibitors, which have already revolutionized melanoma treatment, are a clear priority.     

Caspases: potential targets for regulating cell death

While in multicellular organisms all cells inexorably die, there are several different ways provided for the realization of cell death. One of them, apoptosis, represents a universal energy-dependent and tightly regulated physiologic process of cell death in both normal and pathologic tissues. The execution of apoptosis appears to be uniformly mediated through consecutive activation of the members of a caspase family. This review briefly summarizes current knowledge on the molecular mechanisms of caspase activation and the inhibitory components of caspase cascades. The suitability of caspases as a new potential therapeutic target is discussed next. Particular attention is focused on two broad categories of caspase-directed compounds: highly specific caspase inhibitors that distinctly block the progress of apoptosis and caspase activators that selectively induce cell death in a variety of in vitro and in vivo systems. These agents promise to be useful clinically, either alone or in combination with more conventional therapeutics.     

Gene expression signature of human HepG2 cell line

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is associated with various clinico-pathological characteristics such as genetic mutations and viral infections. Therefore, numerous laboratories look out for identifying always new putative markers for the improvement of HCC diagnosis/prognosis. Many molecular profiling studies investigated gene expression changes related to HCC. HepG2 represents a pure cell line of human liver carcinoma, often used as HCC model due to the absence of viral infection. In this study we compare gene expression profiles associated with HepG2 (as HCC model) and normal hepatocyte cells by microarray technology. Hierarchical cluster analysis of genes evidenced that 2646 genes significantly down-regulated in HepG2 cells compared to hepatocytes whereas a further 3586 genes significantly up-regulated. By using the Ingenuity Pathway Analysis (IPA) program, we have classified the genes that were differently expressed and studied the functional networks correlating these genes in the complete human interactome. Moreover, to confirm the differentially expressed genes as well as the reliability of our microarray data, we performed a quantitative Real time RT-PCR analysis on 9 up-regulated and 11 down-regulated genes, respectively. In conclusion this work i) provides a gene signature of human hepatoma cells showing genes that change their expression as a consequence of liver cancer in the absence of any genetic mutations or viral infection, ii) evidences new differently expressed genes found in our signature compared to previous published studies and iii) suggests some genes on which to focus future studies to understand if they can be used to improve the HCC prognosis/diagnosis.     

Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection

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RNA m6A methylation across the transcriptome

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