NPLOC4 is a Potential Target and a Poor Prognostic Signature in Lung Squamous Cell Carcinoma

Overview

Journal Sci Rep

Specialty Science

Date 2023 Nov 22

PMID 37993584

Authors

Naixue Wang

Dantong Zhu

Yao Liu

Jingran Wu

Meiling Wang

Shanxiu Jin

Fangwei Fu

Baolei Li

Hongjuan Ji

Cheng Du

Zhendong Zheng

Affiliations

Soon will be listed here.

Abstract

Few prognostic biomarkers exist for lung squamous cell carcinoma (LUSC), which has a poor five-year survival rate. Using bioinformatics, this study evaluated NPLOC4 as a prognostic marker for patients with lung squamous cell carcinoma. Shorter survival periods and tumor growth were linked to high NPLOC4 expression.Disulfiram (DSF) combined with copper (Cu) targets NPLOC4 to achieve antitumor effects in lung squamous cell carcinoma. Thus, we investigated the effects of DSF with Cu in LUSC. Gene-set enrichment analysis identified ubiquitin-mediated proteolysis as the NPLOC4-associated mechanism influencing LUSC prognosis. In SK-MES-1 cell lines, DSF + Cu increased K48-linked ubiquitinated protein expression and apoptosis. This study identified NPLOC4 as a prognostic biomarker and a potential therapeutic target for LUSC.

Citing Articles

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Zhou J, Yu B, Guo P, Wang S BMC Cancer. 2024; 24(1):299.

PMID: 38443800 PMC: 10916110. DOI: 10.1186/s12885-024-12052-9.

References

Cui Y, Niu M, Zhang X, Zhong Z, Wang J, Pang D . High expression of valosin-containing protein predicts poor prognosis in patients with breast carcinoma. Tumour Biol. 2015; 36(12):9919-27. DOI: 10.1007/s13277-015-3748-9. View

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379(21):2040-2051. DOI: 10.1056/NEJMoa1810865. View

Yoshino H, Yamada Y, Enokida H, Osako Y, Tsuruda M, Kuroshima K . Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma. PLoS One. 2020; 15(7):e0236119. PMC: 7363112. DOI: 10.1371/journal.pone.0236119. View

Chen D, Cui Q, Yang H, Dou Q . Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006; 66(21):10425-33. DOI: 10.1158/0008-5472.CAN-06-2126. View

Nechushtan H, Hamamreh Y, Nidal S, Gotfried M, Baron A, Shalev Y . A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist. 2015; 20(4):366-7. PMC: 4391770. DOI: 10.1634/theoncologist.2014-0424. View

Shi X, Wu S, Sun J, Liu Y, Zeng X, Liang Z . PD-L1 expression in lung adenosquamous carcinomas compared with the more common variants of non-small cell lung cancer. Sci Rep. 2017; 7:46209. PMC: 5384250. DOI: 10.1038/srep46209. View

Pye V, Beuron F, Keetch C, McKeown C, Robinson C, Meyer H . Structural insights into the p97-Ufd1-Npl4 complex. Proc Natl Acad Sci U S A. 2007; 104(2):467-72. PMC: 1761865. DOI: 10.1073/pnas.0603408104. View

Yamamoto S, Tomita Y, Nakamori S, Hoshida Y, Iizuka N, Okami J . Valosin-containing protein (p97) and Ki-67 expression is a useful marker in detecting malignant behavior of pancreatic endocrine neoplasms. Oncology. 2004; 66(6):468-75. DOI: 10.1159/000079501. View

DeHoratius C, Silver P . Nuclear transport defects and nuclear envelope alterations are associated with mutation of the Saccharomyces cerevisiae NPL4 gene. Mol Biol Cell. 1996; 7(11):1835-55. PMC: 276030. DOI: 10.1091/mbc.7.11.1835. View

10.

Cao H, Yang W, Zheng P . Cytotoxic effect of disulfiram/copper on human cervical cancer cell lines and LGR5-positive cancer stem-like cells. BMC Cancer. 2022; 22(1):521. PMC: 9082913. DOI: 10.1186/s12885-022-09574-5. View

11.

Liu Y, Guan X, Wang M, Wang N, Chen Y, Li B . Disulfiram/Copper induces antitumor activity against gastric cancer via the ROS/MAPK and NPL4 pathways. Bioengineered. 2022; 13(3):6579-6589. PMC: 9278967. DOI: 10.1080/21655979.2022.2038434. View

12.

Majera D, Skrott Z, Chroma K, Merchut-Maya J, Mistrik M, Bartek J . Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway. Cells. 2020; 9(2). PMC: 7072750. DOI: 10.3390/cells9020469. View

13.

Liu X, Wang L, Cui W, Yuan X, Lin L, Cao Q . Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget. 2016; 7(36):58516-58530. PMC: 5295448. DOI: 10.18632/oncotarget.11305. View

14.

Wu X, Xue X, Wang L, Wang W, Han J, Sun X . Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. Eur J Pharmacol. 2018; 827:1-12. DOI: 10.1016/j.ejphar.2018.02.039. View

15.

Collins L, Haines C, Perkel R, Enck R . Lung cancer: diagnosis and management. Am Fam Physician. 2007; 75(1):56-63. View

16.

Yamamoto S, Tomita Y, Hoshida Y, Iizuka N, Monden M, Yamamoto S . Expression level of valosin-containing protein (p97) is correlated with progression and prognosis of non-small-cell lung carcinoma. Ann Surg Oncol. 2004; 11(7):697-704. DOI: 10.1245/ASO.2004.10.018. View

17.

Duan L, Shen H, Zhao G, Yang R, Cai X, Zhang L . Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells. Biochem Biophys Res Commun. 2014; 446(4):1010-6. DOI: 10.1016/j.bbrc.2014.03.047. View

18.

Skrott Z, Majera D, Gursky J, Buchtova T, Hajduch M, Mistrik M . Disulfiram's anti-cancer activity reflects targeting NPL4, not inhibition of aldehyde dehydrogenase. Oncogene. 2019; 38(40):6711-6722. DOI: 10.1038/s41388-019-0915-2. View

19.

Allensworth J, Evans M, Bertucci F, Aldrich A, Festa R, Finetti P . Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol Oncol. 2015; 9(6):1155-68. PMC: 4493866. DOI: 10.1016/j.molonc.2015.02.007. View

20.

Zheng X, Liu Z, Mi M, Wen Q, Wu G, Zhang L . Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer. Front Oncol. 2021; 11:734853. PMC: 8631359. DOI: 10.3389/fonc.2021.734853. View