Targeting the Janus-activated kinase-2-STAT3 signalling pathway in pancreatic cancer using the HSP90 inhibitor ganetespib.

Abstract

BACKGROUND:

Pancreatic cancer (PC) is an aggressive malignancy characterised by chemoresistance. HSP90 is important for stabilisation of proteins, cell signalling and malignant growth. We hypothesised that ganetespib, an HSP90 inhibitor, can inhibit PC cell growth by interfering with multiple signalling cascades, including the Janus-activated kinase (JAK)-STAT pathway, and act synergistically with chemotherapeutic drugs.

METHODS:

The effects of ganetespib were evaluated in ASPC-1, HPAC, MIA PaCA-2 and PANC-1 cell lines using a cell proliferation assay. Effects on the expression of phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK) and JAK-STAT pathways were examined by Western blot. JAK2 and STAT3 were knocked down by transient transfection with JAK2 or STAT3 small interfering RNA. ASPC-1 and HPAC cell lines were tested for sensitivity to ganetespib, 5-fluorouracil/oxaliplatin, and gemcitabine/paclitaxel, alone and in combination, using an in vivo tumour xenograft model.

RESULTS:

Ganetespib significantly decreased cell proliferation in all tested PC cell lines. Ganetespib decreased the activation of extracellular signal-related kinase (ERK), PI3K/AKT, and c-Jun NH2-terminal kinase (JNK) signalling molecules and diminished the activation of STAT3 in an additive manner with isolated downregulation of JAK2 expression. In animal models, ganetespib potentiated the effects of 5-fluouracil/oxaliplatin and gemcitabine/paclitaxel, as measured by tumour volume. Western blot analysis from tumours removed from animals confirmed the effects of ganetespib on PI3K/AKT, ERK and JNK pathways.

CONCLUSIONS:

Ganetespib inhibits the growth of PC cells, an effect associated with downregulation of signalling through the JAK2-STAT3, PI3K/AKT and MAPK pathways. This provides preclinical proof-of-principle that ganetespib enhances the activity of chemotherapeutic agents and warrants further evaluation in PC clinical trials.

• Authors: Ganji Purnachandra Nagaraju, Anya Mezina, Walid L Shaib, Jerome Landry, Bassel F El-Rayes
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 52 Pg. 109-19 (Jan 2016) ISSN: 1879-0852 [Electronic] England
• PMID: 26682870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• STA 9090
• STAT3 Transcription Factor
• STAT3 protein, human
• Triazoles
• Phosphatidylinositol 3-Kinase
• JAK2 protein, human
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Janus Kinase 2 (genetics, metabolism)
• Mice, Nude
• Molecular Targeted Therapy
• Pancreatic Neoplasms (drug therapy, enzymology, genetics, pathology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Triazoles (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays