WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer.
BACKGROUND
WNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated.


OBJECTIVE
This project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer.


METHODS
The impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immunohistochemical studies.


RESULTS
Knockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A mediates resistance to apoptosis in vitro. In our attempt to identify downstream effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly.


CONCLUSIONS
We identified the WNT5A-NFATc2 axis as important mediator of drug resistance in pancreatic cancer.
Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, D-35043 Marburg, Germany.
Heidi
H
Griesmann
Stefanie
S
Ripka
Moritz
M
Pralle
Volker
V
Ellenrieder
Sandra
S
Baumgart
Malte
M
Buchholz
Christian
C
Pilarsky
Daniela
D
Aust
Thomas M
TM
Gress
Patrick
P
Michl
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics
D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin