Geldanamycin induces apoptosis in human gastric carcinomas by affecting multiple oncogenic kinases that have synergic effects with TNF-related apoptosis-inducing ligand

Abstract

Abstract. The aim of the present study was to evaluate the effect of geldanamycin (GA) on the treatment of human gastric carcinomas and to investigate the molecular mechanism that provides the basis for the combination of GA with the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induction strategy. The expression of target proteins at the mRNA level was determined using reverse transcription-polymerase chain reaction (RT-PCR), and apoptosis was evaluated with the terminal deoxynucleotidyl transferase mediated digoxigenin-dUTP nick-end labeling and Annexin V/propidium iodide (PI) staining methods. Phosphorylation of targeted kinases was studied using immunocytochemistry methods, and malignant phenotypes were studied using in vitro assays. GA treatment inhibits proliferation, migration and invasion, and induces apoptosis in human gastric cancer SGC-7901 cells, most likely by decreasing the expression of B-RAF and by phosphorylation of protein kinase B (AKT) and ERK. The inhibitory role of AKT in TRAIL regulation holds considerable potential for achieving a synergic effect in clinical therapy, using a combination of GA treatment and TRAIL induction. The present study provides a basis for the future application of heat shock protein 90 (Hsp90) inhibitors, such as GA, in the clinical treatment of gastric cancer, particularly in combination therapies with TRAIL inducers.

c-FLIP is a target of the E3 ligase deltex1 in gastric cancer

“…These inhibitors act synergistically with TRAIL to induce cell death in various cancers 50 – 52 . As reported for gastric cancer 53 , we found that addition of GA augmented TRAIL-induced apoptosis (Fig. 5 ).…”

Therapeutic potency of heat-shock protein-90 pharmacological inhibitors in the treatment of gastrointestinal cancer, current status and perspectives

“…To further support the regulatory role of HSP90 in cancer cell apoptosis, Chen et al . showed that geldanamycin, an HSP90 inhibitor, induces apoptosis in gastric cancer SGC‐7901 adenoma cells.…”

“…[18] Moreover, HSP90 could also affect TNFmediated NF-kB activity through the IKK complex in which Cdc37 and HSP90 are found to be two members of its components. [20] To further support the regulatory role of HSP90 in cancer cell apoptosis, Chen et al [21] showed that geldanamycin, an HSP90 inhibitor, induces apoptosis in gastric cancer SGC-7901 adenoma cells. Similarly, administration of HSP90 inhibitors, 17AAG and NVP-AUY922, exhibits potent pro-apoptotic functions in cholangiocarcinoma cells.…”

The development of cancers research based on mitochondrial heat shock protein 90

“…We anticipate further testing of mtHsp90 inhibitors in a broader range of cancer types beyond those mentioned in this review. While the efficacy of inhibitors targeting the other Hsp90 protein, such as Ganetespib (STA-9090) and luminespib (AUY922), has been demonstrated in certain cancers, including hepatocellular carcinoma (HCC) ( 192 ), pancreatic cancer (PC) ( 193 ), gastric cancer (GC) ( 194 , 195 ).…”