DHPS-dependent hypusination of eIF5A1/2 is necessary for TGFβ/fibronectin-induced breast cancer metastasis and associates with prognostically unfavorable genomic alterations in TP53

被引：6

作者：

Guth, R. ^{[1
]}

Adamian, Y. ^{[1
]}

Geller, C. ^{[1
]}

Molnar, J. ^{[1
]}

Maddela, J. ^{[1
]}

Kutscher, L. ^{[1
]}

Bhakta, K. ^{[1
]}

Meade, K. ^{[1
]}

Kim, S. L. ^{[1
]}

Agajanian, M. ^{[1
]}

Kelber, J. A. ^{[1
]}

机构：

[1] Calif State Univ Northridge, Dept Biol, Northridge, CA 91330 USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2019年 / 519卷 / 04期

关键词：

DHPS; eIF5A1/2; Breast cancer; TGF beta-mediated metastasis; TP53; EXPRESSION;

D O I：

10.1016/j.bbrc.2019.09.075

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Metastasis is the leading cause of mortality in patients with solid tumors. In this regard, we previously reported that Pseudopodium-Enriched Atypical Kinase One (PEAK1) is necessary for non-canonical Transforming Growth Factor beta (TGF beta) signaling and TGF beta/fibronectin-induced metastasis. Here, we demonstrate that inhibition of DHPS-dependent eIF5A1/2 hypusination blocks PEAK1 and E-Cadherin expression, breast cancer cell viability and TGF beta/fibronectin-induced PEAK1-dependent breast cancer metastasis. Interestingly, TGF beta stimulation of high-grade metastatic breast cancer cells increases and sustains eIF5A1/2 hypusination. We used a suite of bioinformatics platforms to search biochemical/functional interactions and clinical databases for additional control points in eIF5A1/2 and PEAK1-Epithelial to Mesenchymal Transition (EPE) pathways. This effort revealed that interacting EPE genes were enriched for TP53 transcriptional targets and were commonly co-amplified in breast cancer patients harboring inactivating TP53 mutations. Taken together, these results suggest that combinatorial therapies targeting DHPS and protein activities elevated in TP53-mutant breast cancers may reduce systemic tumor burden and improve patient outcomes. (C) 2019 Elsevier Inc. All rights reserved.

引用

页码：838 / 845

页数：8