JNK pathway inhibition selectively primes pancreatic cancer stem cells to TRAIL-induced apoptosis without affecting the physiology of normal tissue resident stem cells.

Abstract

OBJECTIVE:

Successful treatment of solid cancers mandates targeting cancer stem cells (CSC) without impact on the physiology of normal tissue resident stem cells. C-Jun N-terminal kinase (JNK) signaling has been shown to be of importance in cancer. We test whether JNK inhibition would sensitize pancreatic CSCs to induction of apoptosis via low-dose TNFα-related apoptosis-inducing ligand (TRAIL).

DESIGN:

Effects of JNK inhibition (JNKi) were evaluated in vitro in functional assays, through mRNA and protein expression analysis, and in in vivo mouse studies. CSCs were enriched in anoikis-resistant spheroid culture and analyzed accordingly.

RESULTS:

We confirmed that the JNK pathway is an important regulatory pathway in pancreatic cancer stem cells and further found that JNK inhibition downregulates the decoy receptor DcR1 through IL-8 signaling while upregulating pro-apoptotic death receptors DR4/5, thereby sensitizing cells - even with acquired TRAIL-resistance - to apoptosis induction. Treatment of orthotopic pancreatic cancer xenografts with either gemcitabine, JNKi or TRAIL alone for 4 weeks showed only modest effects compared to control, while the combination of JNKi and TRAIL resulted in significantly lower tumor burden (69%; p < 0.04), reduced numbers of circulating tumor cells, and less distant metastatic events, without affecting the general health of the animals.

CONCLUSIONS:

The combination of JNKi and TRAIL significantly impacts on CSCs, but leaves regular tissue-resident stem cells unaffected - even under hypoxic stress conditions. This concept of selective treatment of pancreatic CSCs warrants further evaluation.

• Authors: Alejandro Recio-Boiles, Matthias Ilmer, P Robyn Rhea, Claudia Kettlun, Mitja L Heinemann, Jennifer Ruetering, Jody Vykoukal, Eckhard Alt
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 9 Pg. 9890-906 (Mar 01 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26840266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• TNF-Related Apoptosis-Inducing Ligand
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism)
• Animals
• Anthracenes (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Flow Cytometry
• Humans
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice, Nude
• Microscopy, Fluorescence
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Stem Cells (drug effects, physiology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays