Abstract
Pancreatic cancer has a poor prognosis due to its rapid rate of metastasis and frequent late-stage diagnosis. An improved understanding of the molecular mechanisms underlying this disease is urgently needed to promote the development of improved diagnostic tools and more effective therapies. Apoptosis signal-regulating kinase 1 (ASK1) has been shown to be overexpressed in pancreatic cancer and to promote the proliferation of pancreatic cancer cells in a kinase activity-dependent manner. However, the molecular mechanisms by which ASK1 promotes cell proliferation remain to be elucidated. In this study, we report that the phosphorylation of end-binding protein 1 (EB1) at threonine 206 (pT206-EB1), which is catalyzed by ASK1, is increased in pancreatic cancer tissues. We further find that the level of pT206-EB1 correlates with that of ASK1 in cancer tissues. Additionally, ASK1 localizes to spindle poles, and knockdown of ASK1 results in the formation of multipolar spindles. Moreover, we show that depletion of ASK1 or disruption of EB1 phosphorylation inhibits spindle microtubule dynamics in pancreatic cancer cells. Collectively, these findings suggest that EB1 phosphorylation mediates the functions of ASK1 in pancreatic cancer development.
Highlights
Pancreatic cancer has a very poor prognosis due to its rapid progression and lack of early detection
To understand whether Apoptosis signalregulating kinase 1 (ASK1)-mediated phosphorylation of end-binding protein 1 (EB1) contributes to pancreatic cancer development, we analyzed the expression of ASK1, EB1, and EB1 phosphorylated at T206 in clinical samples from pancreatic cancer patients (Figures 1A-1C)
Our data demonstrate that EB1 phosphorylation mediates the functions of ASK1 in pancreatic cancer development
Summary
Pancreatic cancer has a very poor prognosis due to its rapid progression and lack of early detection. Mutations in a subset of genes, including KRAS, CDKN2A, TP53, and SMAD4, have been found to be associated with pancreatic cancer initiation and development [3]. Aberrant expression or mutation of ASK1 has been implicated in the pathogenesis of cardiovascular and neurodegenerative diseases, diabetes, and cancer [7]. ASK1 overexpression has been shown to play a crucial role in pancreatic cancer development through the promotion of cell proliferation [8]. This oncogenic role has been shown to require the kinase activity of ASK1, but the downstream effectors in the process remain elusive
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