Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells.
Highlights
Eukaryotic translation initiation factor 5A regulates pancreatic cancer pathogenesis
As Eukaryotic translation initiation factor 5A (eIF5A) expression is significantly increased in high grade Pancreatic ductal adenocarcinoma (PDAC) tissues [13], we sought to determine whether eIF5A plays a role in PDAC cell migration and metastasis, which has not been investigated to date
We found that GC7 treatment effectively blocked eIF5A hypusination (Fig. 1B), and significantly reduced migration and invasion of PANC1 cells (Fig. 1B), phenocopying eIF5A knockdown (Fig. 1A)
Summary
Eukaryotic translation initiation factor 5A (eIF5A) regulates pancreatic cancer pathogenesis. MTOR (mammalian target of rapamycin), a regulator of translation commonly implicated in a broad spectrum of human malignancies, may not be critical for oncogenic translation in PDAC, as mTOR inhibition failed to show efficacy in clinical trials [11, 12] These findings suggest that alternative mechanisms operate to modulate oncogenic protein synthesis in PDAC. Proteomic profiling and informatics analyses of eIF5A-depleted human PDAC cell lines revealed networks of cytoskeleton regulatory proteins involved in cell migration and uncovered a functional RhoA/ROCK signaling node that operates downstream of eIF5A in invasive cancer cells. These results indicate that eIF5A activation serves as a rheostat that controls the protein expression of RhoA and ROCK in PDAC cells. EIF5A/RhoA/ROCK module as a possible new therapeutic target in metastatic PDAC cells
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