JNK pathway inhibition selectively primes pancreatic cancer stem cells to TRAIL-induced apoptosis without affecting the physiology of normal tissue resident stem cells
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Alejandro Recio-Boiles1,*, Matthias Ilmer1,*, P. Robyn Rhea2, Claudia Kettlun3, Mitja L. Heinemann1, Jennifer Ruetering1, Jody Vykoukal1 and Eckhard Alt4,5
1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 InGeneron Incorporated, Houston, Texas, USA
4 Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA
5 ISAR Klinikum, Munich, Germany
* These authors have contributed equally to this work
Eckhard Alt, email:
Keywords: pancreatic cancer, cancer stem cells, JNK, TRAIL, apoptosis
Received: March 02, 2015 Accepted: December 12, 2015 Published: January 28, 2016
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.
P. Robyn Rhea
Mitja L. Heinemann
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