Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer

Wang, Ming Chuan; Chang, Ying; Wu, Chih Chieh; Tyan, Yu‐Chang; Chang, Hsung-Pin; Goan, Yih Gang; Lai, Wu‐Wei; Cheng, Pin Nan; Liao, Pao Chi

doi:10.1097/jto.0000000000000396

Cited by 37 publications

(28 citation statements)

References 38 publications

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“…Alpha‐actinin‐4 has been frequently reported to be associated with cell motility and cancer metastasis . In NSCLC, alpha‐actinin‐4 participates in cell migration after secretion and modulates the microenvironment of the cancer cells for tumor development . Furthermore, actinin‐4 has been reported to be a transcriptional co‐activator that enhances or activates other proteins associated with metastasis and cell mobility in lung cancer .…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

Bosse

Haneder²,

Arlt

et al. 2016

Proteomics

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Tyrosine kinase inhibitors, such as erlotinib, display reliable responses and survival benefits for the treatment of human non-small cell lung cancer (NSCLC) patients. However, primary or acquired resistance limits their therapeutic success. In this study, we conducted in-depth mass spectrometric analyses of NSCLC cell secretomes. To identify secreted proteins that are differentially regulated in erlotinib-sensitive (PC-9) and -resistant (PC-9ER) NSCLC cell lines, SILAC experiments were performed. On average, 900 proteins were identified in each sample with low variations in the numbers of identified proteins. Fourteen proteins were found to be differently regulated among erlotinib-sensitive and -resistant NSCLC cell lines, with five proteins (tissue-type plasminogen activator, epidermal growth factor receptor, urokinase-type plasminogen activator, platelet-derived growth factor D, and myeloid-derived growth factor) showing the most prominent regulation. Tissue-type plasminogen activator (t-PA) was up to 10-times upregulated in erlotinib-resistant NSCLC cells compared with erlotinib-sensitive cells. T-PA is an established tumor marker for various cancer types and seems to be a promising prognostic marker to differentiate erlotinib-sensitive from erlotinib-resistant NSCLC cells. To gain further insights into t-PA-regulated pathways, a t-PA variant was expressed in E. coli cells and its interactions with proteins secreted from erlotinib-sensitive and -resistant NCSLC cells were studied by a combined affinity enrichment chemical cross-linking/mass spectrometry (MS) approach. Fourteen proteins were identified as potential t-PA interaction partners, deserving a closer inspection to unravel the mechanisms underlying erlotinib resistance in NSCLC cells.

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Section: Discussionmentioning

confidence: 99%

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

Bosse

Haneder²,

Arlt

et al. 2016

Proteomics

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“…Dynamic actin cytoskeleton remodeling has long been associated with tumor cell migration and invasion (31). It is noteworthy that increased α‐actinin‐4 protein expression levels promote cancer cell invasion and metastasis (32, 33), and that, in most studies, high α‐actinin‐4 protein expression levels correlated with poor outcomes or advanced disease (34). NHERF1 is also related to cancer invasion and metastasis (30).…”

Section: Discussionmentioning

confidence: 99%

NHERF1 regulates actin cytoskeleton organization through modulation of α‐actinin‐4 stability

et al. 2015

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The actin cytoskeleton is composed of a highly dynamic network of filamentous proteins, yet the molecular mechanism that regulates its organization and remodeling remains elusive. In this study, Na + /H + exchanger regulatory factor (NHERF)-1 loss-of-function and gain-of-function experiments reveal that polymerized actin cytoskeleton (F-actin) in HeLa cells is disorganized by NHERF1, whereas actin protein expression levels exhibit no detectable change. To elucidate the molecular mechanism underlying actin cytoskeleton disorganization by NHERF1, a combined 2-dimensional electrophoresismatrix-assisted laser desorption/ionization-time of flight mass spectrometry approach was used to screen for proteins regulated by NHERF1 in HeLa cells. a-Actinin-4, an actin cross-linking protein, was identified. Glutathione S-transferase pull-down and coimmunoprecipitation studies showed the a-actinin-4 carboxyl-terminal region specifically interacted with the NHERF1 postsynaptic density 95/disc-large/zona occludens-1 domain. The NHERF1/ a-actinin-4 interaction increased a-actinin-4 ubiquitination and decreased its expression levels, resulting in actin cytoskeleton disassembly. Our study identified a-actinin-4 as a novel NHERF1 interaction partner and provided new insights into the regulatory mechanism of the actin cytoskeleton by NHERF1

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“…Actinin-4 was investigated as a potential biomarker for the metastatic potential of cancer cells in this study because actinin-4 functions in the production of cellular protrusions that are involved in cancer invasion [16,17,23,24]. Thus, actinin-4 overexpression confers metastatic potential on cancer cells and is closely associated with cancer invasion and metastasis in some kinds of cancers.…”

Section: Discussionmentioning

confidence: 99%

Actinin-4 Protein Overexpression as a Predictive Biomarker in Adjuvant Chemotherapy for Resected Lung Adenocarcinoma

Shiraishi

Fujiwara²,

Kakuya³

et al. 2017

Biomark. Med.

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Aim:Although several clinical trials demonstrated the benefits of platinum-combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma. Materials & methods: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups. Results: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter. Conclusion: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients. Non-small-cell lung cancer (NSCLC) is one of the most lethal malignancies worldwide. Surgical resection is the most potentially curative treatment and is the standard treatment choice for patients with early stage NSCLC. However, despite curative surgery, the 5-year survival of NSCLC patients is 46-64% at stage IIA, about 36-49% at stage IIB and just 25% at stage IIIA [1,2]. Several meta-analyses and randomized controlled trials, including the JBR.10 and ANITA trials, have demonstrated the efficacy of adjuvant chemotherapy for NSCLC patients [3][4][5][6]. Although adjuvant cisplatin-based chemotherapy is recommended as standard care in completely resected NSCLC patients with stage II-IIIA [7,8], the relative reduction in the risk of death of patients undergoing adjuvant chemotherapy is modest in comparison with that of patients without adjuvant chemotherapy (hazard ratio [HR] for stage II: 0.83; 95% CI: 0.73-0.95; and HR for stage III: 0.83; 95% CI: 0.72-0.94). Therefore, the identification of predictive biomarkers for the efficacy of adjuvant chemotherapy for stage II-IIIA is required in the clinical setting. To identify companion diagnostic biomarkers for adjuvant chemotherapy, numerous prognostic factors as well as predictive factors for adjuvant chemotherapy have been investigated for early stage NSCLC [9][10][11][12][13][14].

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Alpha-Actinin 4 Is Associated with Cancer Cell Motility and Is a Potential Biomarker in Non–Small Cell Lung Cancer

Abstract: We demonstrate that the knockdown of ACTN4 protein inhibited cell invasion and migration. These results suggest that ACTN4 is associated with lung cancer cell motility. Thus, the level of ACTN4 in cancerous tissue and plasma is related to the presence of lung cancer.

Cited by 37 publications

References 38 publications

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

NHERF1 regulates actin cytoskeleton organization through modulation of α‐actinin‐4 stability

Actinin-4 Protein Overexpression as a Predictive Biomarker in Adjuvant Chemotherapy for Resected Lung Adenocarcinoma

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