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

Abstract

// Alejandro Recio-Boiles 1,* , Matthias Ilmer 1,* , P. Robyn Rhea 2 , Claudia Kettlun 3 , Mitja L. Heinemann 1 , Jennifer Ruetering 1 , Jody Vykoukal 1 and Eckhard Alt 4,5 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.