thapsigargin 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

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