Oncotarget

Research Papers:

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

Alejandro Recio-Boiles, Matthias Ilmer, P. Robyn Rhea, Claudia Kettlun, Mitja L. Heinemann, Jennifer Ruetering, Jody Vykoukal, Eckhard Alt _

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Abstract

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

Correspondence to:

Eckhard Alt, email:

Keywords: pancreatic cancer, cancer stem cells, JNK, TRAIL, apoptosis

Received: March 02, 2015 Accepted: December 12, 2015 Published: January 28, 2016

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.

Author Information

Alejandro Recio-Boiles

Matthias Ilmer

P. Robyn Rhea

Claudia Kettlun

Mitja L. Heinemann

Jennifer Ruetering

Jody Vykoukal

Eckhard Alt
Primary Contact  _


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