Format

Send to

Choose Destination
Cancer Res. 2017 Apr 15;77(8):1997-2007. doi: 10.1158/0008-5472.CAN-16-2594. Epub 2017 Apr 5.

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth.

Author information

1
Department of Pathology, University of California, San Diego, La Jolla, California.
2
Moores Cancer Center, University of California, San Diego, La Jolla, California.
3
Department of Medicine, University of California, San Diego, La Jolla, California.
4
Department of Pharmacology, University of California, San Diego, La Jolla, California.
5
Department of Biology, California State University Northridge, Northridge, California.
6
Department of Surgery, University of California, San Diego, La Jolla, California.
7
Department of Pathology, University of California, San Diego, La Jolla, California. rklemke@ucsd.edu.

Abstract

In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell-associated transcription factors (STF) including Oct4, Nanog, c-Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity. Cancer Res; 77(8); 1997-2007. ©2017 AACR.

PMID:
28381547
PMCID:
PMC5392372
DOI:
10.1158/0008-5472.CAN-16-2594
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center