A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

Chen, Ching-Hsien; Chuang, Shiow-Shuh; Yang, Meng; Liao, Jiunn‐Wang; Yu, Sung-Liang; Chen, Jeremy J.W.

doi:10.1158/1541-7786.mcr-12-0189

Cited by 88 publications

(97 citation statements)

References 42 publications

(53 reference statements)

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“…3C), MYH9 and NPM1 have been reported to be associated with regional lymph node tumor metastasis (39,40). YWHAZ has been reported to promote epithelial-mesenchymal transition in lung cancer (41). FLNA may promote metastasis by enhancing cell migration in melanoma (42).…”

Section: Resultsmentioning

confidence: 99%

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Wang

Tan

Nguyễn

et al. 2014

Molecular & Cellular Proteomics

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Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drugbinding sites of two protein targets, NF-B and actin. Molecular & Cellular Proteomics 13: 10.1074/mcp. M113.029793, 876-886, 2014.As most drugs exert pharmacological effects by interacting with their target proteins, the identification of these target proteins is a critical step in unraveling the mechanisms of drug action. It is also imperative for our understanding of the pharmacodynamics of a known drug, suggesting potentially unrevealed actions and thus refining future clinical applications of the substance. Traditional approaches used to identify protein targets of a drug typically utilize immobilized drug affinity chromatography coupled with mass spectrometry (MS) 1 (1, 2). These methods can be applied to cell lysates, but not in an in vivo setting, because of the requirement of a solid support. In vitro target profiling might not accurately reflect the drug's actions in the in vivo physiological environment. To overcome this limitation, several groups have used activity-based protein profiling (ABPP) combined with bio-orthogonal click chemistry to identify drug targets both in vitro and in vivo (supplemental Fig. S1) (3-15). ABPP probes exert their functions via covalent reactions with the target proteins or photoaffinity-based labeling via the incorporation of photoreactive groups. With the increasing sensitivity of modern MS platforms, low-abundance protein targets can be successfully identified. Although both conventional affinity chromatography and recent ABPP-based methods allow us to detect a set of candidate protein targets for a drug, it remains difficult to 1 The abbreviations used are: MS, mass spectrometry; ABPP, activity-based protein profiling; ICABPP, clickable activity-based protein profiling; iTRAQ, isobaric tags for relative and absolute quantitation; DMSO, dimethyl sulfoxide; Andro, androgr...

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Section: Resultsmentioning

confidence: 99%

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Wang

Tan

Nguyễn

et al. 2014

Molecular & Cellular Proteomics

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“…YWHAZ is involved in several cellular processes such as cell growth, differentiation, mitosis, and oncogenic transformation [17][18][19]. YWHAZ could serve as a promising prognostic biomarker in localized PCa to predict poor prognosis and to identify a subgroup of tumors [20]. YWHAZ silencing restored doxorubicin-based drug sensitivity in breast cancer cells [21].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer

Hong¹,

Chen²,

Xing³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cancer stem-like cells are the main cause of tumor occurrence, progression, and therapeutic resistance. However, the precise signals required for the maintenance of the stem-like traits of these cells in ovarian cancer remain elusive. We have thus worked to elucidate the functional role of Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, in the regulation of multidrug resistance and stem cell-like traits in ovarian cancer. Methods: We detected the YWHAZ levels in human ovarian cancer specimens and cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blots. MTS assays, soft agar colony formation assays, migration assays, cell cycle analysis, sphere formation assays, and flow cytometry were applied to investigate the functional role of YWHAZ in ovarian cancer. Results: Our data reveals substantially increased YWHAZ expression in both cisplatin- and paclitaxel-resistant ovarian cancer cells. Silencing YWHAZ restored the sensitivity of resistant ovarian cancer cells to cisplatin and paclitaxel. Furthermore, in vitro studies showed that down-regulation of YWHAZ inhibited cell cycle progression, migration, and the expression of stem cell markers. Moreover, tumorigenicity was suppressed in tumor-bearing BALB/c nude mice following YWHAZ knockdown. Additionally, we demonstrated that the expression of YWHAZ was directly down-regulated by miR-30e in resistant ovarian cancer cells. Conclusion: Our results have led to new insights into the essential role of YWHAZ in the regulation of tumourigenesis, stem-like traits, and drug resistance in ovarian cancer, thereby helping to identify a potential target for ovarian cancer therapy.

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“…Among these genes, PARVA was identified as an ideal candidate for further investigation of its role in lung cancer progression because of the significant differences in expression between the highly invasive CL1–5 and less invasive CL1–0 cells as determined by microarray analysis (Fig. 1A, left panel) [23,24]. The differential expression of PARVA was verified by real-time RT-PCR and Western blot analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

PARVA Promotes Metastasis by Modulating ILK Signalling Pathway in Lung Adenocarcinoma

et al. 2015

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α-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony-forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation in vitro. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in in vivo mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3β. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3β. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression.

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A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial–Mesenchymal Transition and Lung Cancer Metastasis

Cited by 88 publications

References 42 publications

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer

PARVA Promotes Metastasis by Modulating ILK Signalling Pathway in Lung Adenocarcinoma

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