Proteomic Profiling of BRAFV600E Mutant Colon Cancer Cells Reveals the Involvement of Nucleophosmin/c-Myc Axis in Modulating the Response and Resistance to BRAF Inhibition by Vemurafenib

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 2

PMID 34201061

Citations 8

Authors

Petra Grbcic

Dora Fuckar cupic

Tania Gamberi

Sandra Kraljevic Pavelic

Mirela Sedic

Affiliations

Soon will be listed here.

Abstract

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.

Citing Articles

Pan-cancer analysis of the prognostic and immunological role of nucleophosmin/nucleoplasmin 3 () and its potential significance in lung adenocarcinoma.

Wei Q, Zhou J, Wang X, Li Z, Chen X, Chen K Cancer Pathog Ther. 2024; 1(4):238-252.

PMID: 38327603 PMC: 10846304. DOI: 10.1016/j.cpt.2023.06.004.

Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib.

Car I, Dittmann A, Klobucar M, Grbcic P, Kraljevic Pavelic S, Sedic M Biology (Basel). 2023; 12(4).

PMID: 37106808 PMC: 10136293. DOI: 10.3390/biology12040608.

RANBP1 (RAN Binding Protein 1): The Missing Genetic Piece in Cancer Pathophysiology and Other Complex Diseases.

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Histone Chaperones and Digestive Cancer: A Review of the Literature.

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Proteomic characterization of post-translational modifications in drug discovery.

Zhai L, Chen K, Hao B, Tan M Acta Pharmacol Sin. 2022; 43(12):3112-3129.

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References

Sun W, Kim H, Jung W, Koo J . Expression of serine/glycine metabolism-related proteins is different according to the thyroid cancer subtype. J Transl Med. 2016; 14(1):168. PMC: 4898323. DOI: 10.1186/s12967-016-0915-8. View

Coffee E, Faber A, Roper J, Sinnamon M, Goel G, Keung L . Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res. 2013; 19(10):2688-98. PMC: 3815598. DOI: 10.1158/1078-0432.CCR-12-2556. View

Tedeschi A, Ciciarello M, Mangiacasale R, Roscioli E, Rensen W, Lavia P . RANBP1 localizes a subset of mitotic regulatory factors on spindle microtubules and regulates chromosome segregation in human cells. J Cell Sci. 2007; 120(Pt 21):3748-61. DOI: 10.1242/jcs.009308. View

Hashimoto N, Nagano H, Tanaka T . The role of tumor suppressor p53 in metabolism and energy regulation, and its implication in cancer and lifestyle-related diseases. Endocr J. 2019; 66(6):485-496. DOI: 10.1507/endocrj.EJ18-0565. View

Lai E, Pretta A, Impera V, Mariani S, Giampieri R, Casula L . BRAF-mutant colorectal cancer, a different breed evolving. Expert Rev Mol Diagn. 2018; 18(6):499-512. DOI: 10.1080/14737159.2018.1470928. View

Frazier M, He X, Wang J, Gu Z, Cleveland J, Zambetti G . Activation of c-myc gene expression by tumor-derived p53 mutants requires a discrete C-terminal domain. Mol Cell Biol. 1998; 18(7):3735-43. PMC: 108956. DOI: 10.1128/MCB.18.7.3735. View

Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M . A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell. 2016; 165(2):317-30. DOI: 10.1016/j.cell.2016.02.059. View

Li Z, Hann S . Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene. 2012; 32(15):1988-94. PMC: 3855075. DOI: 10.1038/onc.2012.227. View

Lopez D, Rodriguez J, Banuelos S . Nucleophosmin, a multifunctional nucleolar organizer with a role in DNA repair. Biochim Biophys Acta Proteins Proteom. 2020; 1868(12):140532. DOI: 10.1016/j.bbapap.2020.140532. View

10.

Schmidt E . The role of c-myc in regulation of translation initiation. Oncogene. 2004; 23(18):3217-21. DOI: 10.1038/sj.onc.1207548. View

11.

Morris V, Bekaii-Saab T . Improvements in Clinical Outcomes for -Mutant Metastatic Colorectal Cancer. Clin Cancer Res. 2020; 26(17):4435-4441. DOI: 10.1158/1078-0432.CCR-19-3809. View

12.

Hutton J, Wang X, Zimmerman L, Slebos R, Trenary I, Young J . Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer. Mol Cell Proteomics. 2016; 15(9):2924-38. PMC: 5013308. DOI: 10.1074/mcp.M116.058925. View

13.

Zhang M, Arnaoutov A, Dasso M . RanBP1 governs spindle assembly by defining mitotic Ran-GTP production. Dev Cell. 2014; 31(4):393-404. PMC: 4254504. DOI: 10.1016/j.devcel.2014.10.014. View

14.

Barras D, Missiaglia E, Wirapati P, Sieber O, Jorissen R, Love C . BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression. Clin Cancer Res. 2016; 23(1):104-115. DOI: 10.1158/1078-0432.CCR-16-0140. View

15.

Kim M, Kim J, Hong H, Lee S, Lee J, Jung E . Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2015; 35(5):462-78. PMC: 4772854. DOI: 10.15252/embj.201592081. View

16.

Mossmann D, Park S, Hall M . mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018; 18(12):744-757. DOI: 10.1038/s41568-018-0074-8. View

17.

Singleton K, Crawford L, Tsui E, Manchester H, Maertens O, Liu X . Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence. Cell Rep. 2017; 21(10):2796-2812. PMC: 5728698. DOI: 10.1016/j.celrep.2017.11.022. View

18.

Zeller K, Haggerty T, Barrett J, Guo Q, Wonsey D, Dang C . Characterization of nucleophosmin (B23) as a Myc target by scanning chromatin immunoprecipitation. J Biol Chem. 2001; 276(51):48285-91. DOI: 10.1074/jbc.M108506200. View

19.

Fritsche-Guenther R, Zasada C, Mastrobuoni G, Royla N, Rainer R, Rossner F . Alterations of mTOR signaling impact metabolic stress resistance in colorectal carcinomas with BRAF and KRAS mutations. Sci Rep. 2018; 8(1):9204. PMC: 6003911. DOI: 10.1038/s41598-018-27394-1. View

20.

Kulshrestha A, Suman S, Ranjan R . Network analysis reveals potential markers for pediatric adrenocortical carcinoma. Onco Targets Ther. 2016; 9:4569-81. PMC: 4968868. DOI: 10.2147/OTT.S108485. View