Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration

Zheng, Xiangqian; Chi, Jiadong; Jiang, Zhi; Zhang, H; Yue, Dongsheng; Zhao, Jingzhu; Li, D; Li, Y; Gao, Ming; Guo, Jianping

doi:10.1038/onc.2017.354

Cited by 38 publications

(30 citation statements)

References 45 publications

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“…Many researchers have found that four key genes were involved in cell cycle, participating in tumorigenesis and tumor proliferation. AURKA has been studied in a wide range of human malignancies and is associated with poor prognosis in several malignancies, including cervical squamous cell carcinoma, hepatocellular carcinoma, and nonsmall cell lung carcinoma (Ma et al, ; Wang et al, ; Zheng et al, ). Besides, Yang et al, () reported that AURKA as a transactivating co‐factor in the induction of the c‐Myc oncoprotein in breast cancer stem cells (BCSCs).…”

Section: Discussionmentioning

confidence: 99%

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

Chen¹,

Wang

Shen

et al. 2019

Molec Gen & Gen Med

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Background Colorectal cancer (CRC) is one of the most common malignant tumors. In the present study, the expression profile of human multistage colorectal mucosa tissues, including healthy, adenoma, and adenocarcinoma samples was downloaded to identify critical genes and potential drugs in CRC. Methods Expression profiles, GSE33113 and GSE44076, were integrated using bioinformatics methods. Differentially expressed genes (DEGs) were analyzed by R language. Functional enrichment analyses of the DEGs were performed using the Database for Annotation, visualization, and integrated discovery (DAVID) database. Then, the search tool for the retrieval of interacting genes (STRING) database and Cytoscape were used to construct a protein–protein interaction (PPI) network and identify hub genes. Subsequently, survival analysis was performed among the key genes using Gene Expression Profiling Interactive Analysis (GEPIA). Connectivity Map (CMap) was used to query potential drugs for CRC. Results A total of 428 upregulated genes and 751 downregulated genes in CRC were identified. The functional changes of these DEGs were mainly associated with cell cycle, oocyte meiosis, DNA replication, p53 signaling pathway, and progesterone‐mediated oocyte maturation. A PPI network was identified by STRING with 482 nodes and 2,368 edges. Survival analysis revealed that high mRNA expression of AURKA, CCNB1, CCNF, and EXO1 was significantly associated with longer overall survival. Moreover, CMap predicted a panel of small molecules as possible adjuvant drugs to treat CRC. Conclusion Our study found key dysregulated genes involved in CRC and potential drugs to combat it, which may provide novel insights and potential biomarkers for prognosis, as well as providing new CRC treatments.

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Section: Discussionmentioning

confidence: 99%

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

Chen¹,

Wang

Shen

et al. 2019

Molec Gen & Gen Med

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“…Inflammation is a contributor to NSCLC progression [10–12], and C5a can cause tumor cell proliferation [8, 9, 28, 29]. However, how C5a affects tumor cell proliferation in NSCLC still remains obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have revealed that C5a is associated with tumor growth [4, 5], and C5a in tumor microenvironment not only acts as a leukocyte chemoattractant [4, 5], but also promotes tumor cell proliferation [6–8]. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer [9]. Although many researchers have uncovered that inflammatory cytokines or mediators, e.g., C5a are involved in NSCLC carcinogenesis and proliferation [10–12], the mechanism of C5a governing NSCLC cell proliferation remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Zhao

Qiu

et al. 2018

Oncogene

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.

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“…Although AMPK regulates mTOR as part of the mTOR complex 1 (mTORC1) and AKT S473 is an mTORC2 target site, it has been recently shown that AMPK activation can also reduce mTORC2 activity and AKT S473 phosphorylation in NSCLC cells (55). Interestingly, recent studies found that inhibition of AURKA can overcome mTOR inhibitor resistance in gastrointestinal cancer cells and that AURKA can repress STK11(LKB1)/AMPK signaling in NSCLC cells (56,57). These data agree with our findings that AURKA inhibition is a major component of midostaurin's MoA, maybe even more so in STK11-wild-type cells.…”

Section: Molecular and Cellular Proteomics 1712 2443mentioning

confidence: 99%

Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells

Ctortecka

Palve

Kuenzi

et al. 2018

Molecular & Cellular Proteomics

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Lung cancer is associated with high prevalence and mortality, and despite significant successes with targeted drugs in genomically defined subsets of lung cancer and immunotherapy, the majority of patients currently does not benefit from these therapies. Through a targeted drug screen, we found the recently approved multi-kinase inhibitor midostaurin to have potent activity in several lung cancer cells independent of its intended target, PKC, or a specific genomic marker. To determine the underlying mechanism of action we applied a layered functional proteomics approach and a new data integration method. Using chemical proteomics, we identified multiple midostaurin kinase targets in these cells. Network-based integration of these targets with quantitative tyrosine and global phosphoproteomics data using protein-protein interactions from the STRING database suggested multiple targets are relevant for the mode of action of midostaurin. Subsequent functional validation using RNA interference and selective small molecule probes showed that simultaneous inhibition of TBK1, PDPK1 and AURKA was required to elicit midostaurin's cellular effects. Immunoblot analysis of downstream signaling nodes showed that combined inhibition of these targets altered PI3K/AKT and cell cycle signaling pathways that in part converged on PLK1. Furthermore, rational combination of midostaurin with the potent PLK1 inhibitor BI2536 elicited strong synergy. Our results demonstrate that combination of complementary functional proteomics approaches and subsequent network-based data integration can reveal novel insight into the complex mode of action of multi-kinase inhibitors, actionable targets for drug discovery and cancer vulnerabilities. Finally, we illustrate how this knowledge can be used for the rational design of synergistic drug combinations with high potential for clinical translation.

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Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration

Cited by 38 publications

References 45 publications

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

Identification of novel biomarkers and small molecule drugs in human colorectal cancer by microarray and bioinformatics analysis

C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation

Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells

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