interleukin-8 and apicidin

Interleukin-8 (IL-8) and heat shock protein 60 (Hsp60) play crucial roles in cell survival and maintenance of cellular homoeostasis. However, cross talks between these two proteins are not defined.. IL-8 expression in tumour tissue sections was analysed by immunohistochemistry. IL-8 expression and release in cancer cells was quantified using enzyme-linked immunosorbent assay (ELISA). Apoptosis was quantified using caspase activity and Annexin-V/PI staining.. We observed IL-8 release from cancer cells in response to histone deacetylase inhibitor, apicidin (Api), and non-competitive inhibitor of the sarco/endoplasmic reticulum Ca. This study describes the underlying mechanism associated with apoptosis resistance mediated via Hsp60-IL-8 axis in cancer.

Topics: Animals; Apoptosis; Caspase 8; Caspase 9; Chaperonin 60; Gene Knockdown Techniques; HCT116 Cells; Heterografts; Humans; Interleukin-8; Male; Mice; Mice, SCID; Mitochondrial Proteins; Neoplasms; PC-3 Cells; Peptides, Cyclic; Signal Transduction; Thapsigargin

Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by tissue fibrosis and immune abnormalities. Recent evidence suggests that activated circulating monocytes from patients with SSc play an important role in early stages of SSc pathogenesis due to enhanced expression of tissue inhibitor of metalloproteinases 1 (TIMP-1), IL-8 and reactive oxygen species (ROS) induction. However, the exact factors that contribute to chronic inflammation and subsequently fibrosis progression are still unknown.. The expression pattern of IL-8, TIMP-1, AP-1 transcription factor-Fra2 and ROS induction in peripheral blood monocytes following DZNep (histone methyltransferase inhibitor) and TLR8 agonist stimulation was investigated. Exogenous microRNA-5196, which is predicted to bind 3'UTR of Fra2 gene, was delivered to reverse profibrotic phenotype in monocytes. Expression of circulating microRNA-5196 was correlated with SSc parameters.. DZNep + TLR8 agonist stimulation enhanced profibrotic TIMP-1, IL-8 and ROS generation in HC and SSc monocytes. As opposed by the decrease of miRNA-5196 and antioxidant SOD1 expression in SSc monocytes. Exogenous delivery of microRNA-5196 reduced Fra2 and TIMP-1 expression suggesting that it may be used as a potential modulator of fibrogenesis in SSc. Circulating microRNA-5196 was significantly increased in SSc and positively correlated with CRP level but not with Rodnan skin score or ESR.. These results suggest that microRNA-5196 can be used as a potential biomarker characterising SSc. Overall, this study may open new possibilities for the development of microRNA-5196-based diagnostics and therapy in early phases of SSc.

Topics: Adenosine; Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Female; Fos-Related Antigen-2; Histone Deacetylase Inhibitors; Humans; Interleukin-8; Leukocytes, Mononuclear; Male; Matrix Metalloproteinases; MicroRNAs; Middle Aged; Oxidative Stress; Peptides, Cyclic; Reactive Oxygen Species; Scleroderma, Systemic; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 8; Transfection

Development of therapeutic resistance is responsible for most prostate cancer (PCa) related mortality. Resistance has been attributed to an acquired or selected cancer stem cell phenotype. Here we report the histone deacetylase inhibitor apicidin (APC) or ER stressor thapsigargin (TG) potentiate paclitaxel (TXL)-induced apoptosis in PCa cells and limit accumulation of cancer stem cells. TXL-induced responses were modulated in the presence of TG with increased accumulation of cells at G1-phase, rearrangement of the cytoskeleton, and changes in cytokine release. Cytoskeletal rearrangement was associated with modulation of the cytoplasmic and mitochondrial unfolded protein response leading to mitochondrial dysfunction and release of proapoptotic proteins from mitochondria. TXL in combination with APC or TG enhanced caspase activation. Importantly, TXL in combination with TG induced caspase activation and apoptosis in X-ray resistant LNCaP cells. Increased release of transforming growth factor-beta (TGF-β) was observed while phosphorylated β-catenin level was suppressed with TXL combination treatments. This was accompanied by a decrease in the CD44(+)CD133(+) cancer stem cell-like population, suggesting treatment affects cancer stem cell properties. Taken together, combination treatment with TXL and either APC or TG induces efficient apoptosis in both proliferating and cancer stem cells, suggesting this therapeutic combination may overcome drug resistance and recurrence in PCa.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; beta Catenin; Caspases; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cytoskeleton; Enzyme Activation; G1 Phase; G2 Phase; HSP70 Heat-Shock Proteins; Humans; Interferon-gamma; Interleukin-8; Male; Matrix Metalloproteinases; Membrane Potential, Mitochondrial; Mitochondria; Neoplastic Stem Cells; Paclitaxel; Peptides, Cyclic; Phosphorylation; Prostatic Neoplasms; Reactive Oxygen Species; Thapsigargin; Transforming Growth Factor beta; Unfolded Protein Response; X-Rays

Histone deacetylase (HDAC) inhibitors are promising anti-cancer drugs, but these exert differential responses depending on the cell types. Here, we demonstrate a new mechanism for activation of nuclear factor-kappaB (NF-kappaB) by HDAC inhibitor apicidin and the role of NF-kappaB signaling pathway for mediating differential cellular responses, especially, apoptosis. Treatment of HeLa cells with apicidin increases transcriptional activity of NF-kappaB and its target gene IL-8 and cIAP-1 induction, which involves the activation of IKK-IkappaBalpha signaling pathway through Sp1-dependent de novo protein synthesis. In parallel, apicidin treatment leads to histone hyperacetylation in the IL-8 promoter region independent of NF-kappaB signaling pathway, which is not sufficient for full transcription of IL-8 gene. This NF-kappaB activation contributes to resistance of HeLa cells to apoptotic potential of apicidin. Collectively, our results suggest that activation of NF-kappaB signaling cascade functions as a critical modulator to determine cell fate on apoptosis in response to HDAC inhibitors.

Topics: Apoptosis; Female; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; HeLa Cells; Histone Deacetylase Inhibitors; Humans; I-kappa B Kinase; Inhibitor of Apoptosis Proteins; Interleukin-8; NF-kappa B; Peptides, Cyclic; Signal Transduction; Sp1 Transcription Factor

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.

Topics: Androstadienes; Butadienes; Chromones; Flavonoids; HeLa Cells; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Interleukin-8; Morpholines; NF-kappa B; Nitriles; Peptides, Cyclic; Phosphatidylinositol 3-Kinases; Protein Kinase C; Repressor Proteins; Signal Transduction; Tumor Necrosis Factor-alpha; Wortmannin