Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer.
Adaptor Proteins, Signal Transducing
/ genetics
Biomarkers, Tumor
/ genetics
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Line, Tumor
Cell Proliferation
Cell Survival
Computational Biology
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ genetics
Male
Neoplasm Staging
Prognosis
Survival Analysis
Tissue Array Analysis
Up-Regulation
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
11
12
2019
accepted:
01
05
2020
revised:
19
04
2020
pubmed:
23
5
2020
medline:
26
2
2021
entrez:
23
5
2020
Statut:
ppublish
Résumé
Non-small cell lung cancers (NSCLC) account for 85-90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC. The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences. Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis. Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.
Sections du résumé
BACKGROUND
Non-small cell lung cancers (NSCLC) account for 85-90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC.
METHODS
The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences.
RESULTS
Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis.
CONCLUSIONS
Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.
Identifiants
pubmed: 32439936
doi: 10.1038/s41416-020-0899-2
pii: 10.1038/s41416-020-0899-2
pmc: PMC7434762
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
591-603Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1091589
Commentaires et corrections
Type : ErratumIn
Références
Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., Parkin, D. M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 127, 2893–2917 (2010).
Torre, L. A., Siegel, R. L. & Jemal, A. Lung cancer statistics. Adv. Exp. Med Biol. 893, 1–19 (2016).
pubmed: 26667336
Fitzmaurice, C., Akinyemiju, T. F., Al Lami, F. H., Alam, T., Alizadeh-Navaei, R., Allen, C. et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 4, 1553–1568 (2018).
pubmed: 29860482
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
pubmed: 30207593
pmcid: 30207593
Zhang, L., Wang, L., Du, B., Wang, T., Tian, P. & Tian, S. Classification of non-small cell lung cancer using significance analysis of microarray-gene set reduction algorithm. BioMed. Res. Int. 2016, 2491671–2491671 (2016).
pubmed: 27446945
pmcid: 4944087
Reck, M., Popat, S., Reinmuth, N., De Ruysscher, D., Kerr, K. M., Peters, S. et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25, iii27–iii39 (2014).
pubmed: 25115305
Hirsch, F. R., Scagliotti, G. V., Mulshine, J. L., Kwon, R., Curran, W. J. Jr., Wu, Y. L. et al. Lung cancer: current therapies and new targeted treatments. Lancet 389, 299–311 (2017).
Fennell, D. A., Summers, Y., Cadranel, J., Benepal, T., Christoph, D. C., Lal, R. et al. Cisplatin in the modern era: the backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat. Rev. 44, 42–50 (2016).
pubmed: 26866673
Chang, A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer 71, 3–10 (2011).
pubmed: 20951465
Parashar, B., Arora, S. & Wernicke, A. G. Radiation therapy for early stage lung cancer. Semin. Interven. Radiol. 30, 185–190 (2013).
Bhalla, N., Brooker, R. & Brada, M. Combining immunotherapy and radiotherapy in lung cancer. J. Thorac. Dis. 10, S1447–S1460 (2018).
pubmed: 29951296
pmcid: 5994496
Rocco, D., Della, G. L., Battiloro, C. & Gridelli, C. The role of combination chemo-immunotherapy in advanced non-small cell lung cancer. Expert Rev. Anticancer Ther. https://doi.org/10.1080/14737140.2019.1631800 (2019).
van de Sluis, B., Mao, X., Zhai, Y., Groot, A. J., Vermeulen, J. F., van der Wall, E. et al. COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion. J. Clin. Investig. 120, 2119–2130 (2010).
pubmed: 20458141
Fernandez, M. J. R., Oliva, A. B., Tejeda, Y., Astrada, S., Garay, H., Reyes, O. et al. The antitumor peptide CIGB-552 increases COMMD1 and inhibits growth of human lung cancer cells. J. Amino Acids 2013, 251398 (2013).
Maine, G. N. & Burstein, E. COMMD proteins: COMMing to the scene. Cell Mol. Life Sci. 64, 1997–2005 (2007).
pubmed: 17497243
pmcid: 2938186
Burstein, E., Hoberg, J. E., Wilkinson, A. S., Rumble, J. M., Csomos, R. A., Komarck, C. M. et al. COMMD proteins, a novel family of structural and functional homologs of MURR1. J. Biol. Chem. 280, 22222–22232 (2005).
pubmed: 15799966
Ryan, S.-L., Beard, S., Barr, M. P., Umezawa, K., Heavey, S., Godwin, P. et al. Targeting NF-kappaB-mediated inflammatory pathways in cisplatin-resistant NSCLC. Lung Cancer 135, 217–227 (2019).
pubmed: 31446998
Zheng, L., You, N., Huang, X., Gu, H., Wu, K., Mi, N. et al. COMMD7 regulates NF-kappaB signaling pathway in hepatocellular carcinoma stem-like cells. Mol. Ther. Oncolytics 12, 112–123 (2019).
pubmed: 30719501
Fan, Y., Zhang, L., Sun, Y., Yang, M., Wang, X., Wu, X. et al. Expression profile and bioinformatics analysis of COMMD10 in BALB/C mice and human. Cancer Gene Ther. https://doi.org/10.1038/s41417-019-0087-9 (2019).
Zhan, W., Wang, W., Han, T., Xie, C., Zhang, T., Gan, M. et al. COMMD9 promotes TFDP1/E2F1 transcriptional activity via interaction with TFDP1 in non-small cell lung cancer. Cell Signal. 30, 59–66 (2017).
pubmed: 27871936
Greene, W. C. How resting T cells deMURR HIV infection. Nat. Immunol. 5, 18–19 (2004).
pubmed: 14699403
Mao, X., Gluck, N., Chen, B., Starokadomskyy, P., Li, H., Maine, G. N. et al. COMMD1 (copper metabolism MURR1 domain-containing protein 1) regulates Cullin RING ligases by preventing CAND1 (Cullin-associated Nedd8-dissociated protein 1) binding. J. Biol. Chem. 286, 32355–32365 (2011).
pubmed: 21778237
pmcid: 3173175
Ramirez, R. D., Sheridan, S., Girard, L., Sato, M., Kim, Y., Pollack, J. et al. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 64, 9027–9034 (2004).
pubmed: 15604268
Suraweera, A., Becherel, O. J., Chen, P., Rundle, N., Woods, R., Nakamura, J. et al. Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage. J. Cell Biol. 177, 969–979 (2007).
pubmed: 17562789
pmcid: 2064358
Adams, M. N., Burgess, J. T., He, Y., Gately, K., Snell, C., Zhang, S. D. et al. Expression of CDCA3 is a prognostic biomarker and potential therapeutic target in non-small cell lung cancer. J. Thorac. Oncol. 12, 1071–1084 (2017).
pubmed: 28487093
Oike, T., Komachi, M., Ogiwara, H., Amornwichet, N., Saitoh, Y., Torikai, K. et al. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe. Radiother. Oncol. 111, 222–227 (2014).
pubmed: 24746574
Antonsson, A. & Persson, J. L. Induction of apoptosis by staurosporine involves the inhibition of expression of the major cell cycle proteins at the G(2)/m checkpoint accompanied by alterations in Erk and Akt kinase activities. Anticancer Res. 29, 2893–2898 (2009).
pubmed: 19661292
Pozarowski, P. & Darzynkiewicz, Z. Analysis of cell cycle by flow cytometry. Methods Mol. Biol. 281, 301–311 (2004).
pubmed: 15220539
Gyorffy, B., Surowiak, P., Budczies, J. & Lanczky, A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS ONE 8, e82241 (2013).
pubmed: 3867325
pmcid: 3867325
Collins, F. S. & Barker, A. D. Mapping the cancer genome. Pinpointing the genes involved in cancer will help chart a new course across the complex landscape of human malignancies. Sci. Am. 296, 50–57 (2007).
pubmed: 17348159
Castedo, M., Perfettini, J.-L., Roumier, T., Andreau, K., Medema, R. & Kroemer, G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 23, 2825–2837 (2004).
pubmed: 15077146
Mc Gee, M. M. Targeting the mitotic catastrophe signaling pathway in cancer. Mediators Inflamm. 2015, 13 (2015).
Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E. S., Baehrecke, E. H. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).
pubmed: 18846107
Perez, C. A., Pajak, T. F., Rubin, P., Simpson, J. R., Mohiuddin, M., Brady, L. W. et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer 59, 1874–18811987 (1987).
pubmed: 3032394
Provencio, M., Isla, D., Sánchez, A. & Cantos, B. Inoperable stage III non-small cell lung cancer: current treatment and role of vinorelbine. J. Thorac. Dis. 3, 197–204 (2011).
pubmed: 22263088
pmcid: 3256525
Kobayashi, D., Oike, T., Shibata, A., Niimi, A., Kubota, Y., Sakai, M. et al. Mitotic catastrophe is a putative mechanism underlying the weak correlation between sensitivity to carbon ions and cisplatin. Sci. Rep. 7, 40588 (2017).
pubmed: 28091564
pmcid: 5238371
Chen, P. C., Lavin, M. F., Kidson, C. & Moss, D. Identification of ataxia telangiectasia heterozygotes, a cancer prone population. Nature 274, 484–486 (1978).
pubmed: 672974
Chiu, Y. H., Hsu, S. H., Hsu, H. W., Huang, K. C., Liu, W., Wu, C. Y. et al. Human nonsmall cell lung cancer cells can be sensitized to camptothecin by modulating autophagy. Int J. Oncol. 53, 1967–1979 (2018).
pubmed: 30106130
pmcid: 6192723
Liu, L. F., Desai, S. D., Li, T. K., Mao, Y., Sun, M. & Sim, S. P. Mechanism of action of camptothecin. Ann. NY Acad. Sci. 922, 1–10 (2000).
pubmed: 11193884
Kaufmann, S. H., Desnoyers, S., Ottaviano, Y., Davidson, N. E. & Poirier, G. G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 53, 3976–3985 (1993).
pubmed: 8358726
Ridge, C. A., McErlean, A. M. & Ginsberg, M. S. Epidemiology of lung cancer. Semin Interv. Radiol. 30, 93–98 (2013).
Coate, L. E., John, T., Tsao, M.-S. & Shepherd, F. A. Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol. 10, 1001–1010 (2009).
pubmed: 19796752
Zhu, C.-Q. & Tsao, M.-S. Prognostic markers in lung cancer: is it ready for prime time? Transl. Lung Cancer Res. 3, 149–158 (2014).
pubmed: 25806294
pmcid: 4367687
Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007).
pubmed: 17318210
Simonetti, S., Molina, M. A., Queralt, C., de Aguirre, I., Mayo, C., Bertran-Alamillo, J. et al. Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer. J. Transl. Med. 8, 135–13 (2010).
pubmed: 21167064
pmcid: 3016260
Fragkos, M. & Beard, P. Mitotic catastrophe occurs in the absence of apoptosis in p53-null cells with a defective G1 checkpoint. PLoS ONE 6, e22946–e22946 (2011).
pubmed: 21853057
pmcid: 3154265
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
pubmed: 5864239
pmcid: 5864239
Liu, S., Kwon, M., Mannino, M., Yang, N., Renda, F., Khodjakov, A. et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561, 551–555 (2018).
pubmed: 30232450
pmcid: 6599625
Mouillet, G., Monnet, E., Milleron, B., Puyraveau, M., Quoix, E., David, P. et al. Pathologic complete response to preoperative chemotherapy predicts cure in early-stage non-small-cell lung cancer: combined analysis of two IFCT randomized trials. J Thorac. Oncol. 7, 841–849 (2012).
Lee, J. S., Hirsh, V., Park, K., Qin, S., Blajman, C. R., Perng, R. P. et al. Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J. Clin. Oncol. 30, 1114–1121 (2012).
pubmed: 22370318
Brewer, G. J. Anticopper therapy against cancer and diseases of inflammation and fibrosis. Drug Disco. Today 10, 1103–1109 (2005).
Saha, B., Mukherjee, A., Samanta, S., Paul, S., Bhattacharya, D., Santra, C. R. et al. A novel Cu(ii)–mal–picoline complex induces mitotic catastrophe mediated by deacetylation of histones and α-tubulin leading to apoptosis in human cell lines. MedChemComm 3, 1393–1405 (2012).
Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat. Genet. 27, 247–254 (2001).
pubmed: 11242102
Kelley, M. R., Logsdon, D., Fishel, M. L. & Targeting, D. N. A. repair pathways for cancer treatment: what’s new? Future Oncol. 10, 1215–1237 (2014).
pubmed: 24947262
pmcid: 4125008
Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).
pubmed: 11357144
Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
pubmed: 2906700
pmcid: 2906700
Suraweera, A., Gandhi, N. S., Beard, S., Burgess, J. T., Naqi, A., Bolderson, E. et al. COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double strand breaks. Cell Rep. https://doi.org/10.2139/ssrn.3516893 (2020).