{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:02Z","timestamp":1787027762004,"version":"build-2736575974"},"reference-count":87,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Technology and the Enabling Biotechnology programs at NTNU, Trondheim, Norway","award":["295910"],"award-info":[{"award-number":["295910"]}]},{"name":"Joint Research Committee between St. Olavs and Faculty of Medicine and Health Science, NTNU","award":["295910"],"award-info":[{"award-number":["295910"]}]},{"name":"APIM Therapeutics AS","award":["295910"],"award-info":[{"award-number":["295910"]}]},{"name":"RCN INFRASTRUKTUR-program","award":["295910"],"award-info":[{"award-number":["295910"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Objectives: To examine the regulatory role of PCNA in MM, we have targeted PCNA with the experimental drug ATX-101 in three commercial cell lines (JJN3, RPMI 1660, AMO) and seven in-house patient-derived cell lines with a more primary cell-like phenotype (TK9, 10, 12, 13, 14, 16 and 18) and measured the systemic molecular effects. Methods: We have used a multi-omics untargeted approach, measuring the gene expression (transcriptomics), a subproteomics approach measuring mainly signalling proteins and proteins in complex with these (signallomics) and quantitative metabolomics. These results are supplemented with traditional analysis, e.g., viability, Western and ELISA analysis. Results: The sensitivity of the cell lines to ATX-101 varied, including between three cell lines derived from the same patient at different times of disease. A trend towards increased sensitivity to ATX-101 during disease progression was detected. Although with different sensitivities, ATX-101 treatment resulted in numerous changes in signalling and metabolite pools in all cell lines. Transcriptomics and signallomics analysis of the TK cell lines revealed that elevated endogenous expression of ribosomal genes, elevated proteasomal and endoplasmic reticulum (ER) stress and low endogenous levels of NAD+ and NADH were associated with ATX-101 hypersensitivity. ATX-101 treatment further enhanced the ER stress, reduced primary metabolism and reduced the levels of the redox pair GSH\/GSSG in sensitive cells. Signallome analysis suggested that eleven proteins (TPD52, TNFRS17\/BCMA, LILRB4\/ILT3, TSG101, ZNRF2, UPF3B, FADS2, C11orf38\/SMAP, CGREF1, GAA, COG4) were activated only in the sensitive MM cell lines (TK13, 14 and 16 and JJN3), and not in nine other cancer cell lines or in primary monocytes. These proteins may therefore be biomarkers of cells with activated proteasomal and ER stress even though the gene expression levels of these proteins were not elevated. Interestingly, carfilzomib-resistant cells were at least as sensitive to ATX-101 as the wild-type cells, suggesting both low cross-resistance between ATX-101 and proteasome inhibitors and elevated proteasomal stress in carfilzomib-resistant cells. Conclusions: Our multi-omics approach revealed a vital role of PCNA in regulation of proteasomal and ER stress in MM.<\/jats:p>","DOI":"10.3390\/cancers16233963","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T07:40:32Z","timestamp":1732606832000},"page":"3963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multiple Myeloma Cells with Increased Proteasomal and ER Stress Are Hypersensitive to ATX-101, an Experimental Peptide Drug Targeting PCNA"],"prefix":"10.3390","volume":"16","author":[{"given":"Camilla","family":"Olaisen","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa Marie","family":"R\u00f8st","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8791-4635","authenticated-orcid":false,"given":"Animesh","family":"Sharma","sequence":"additional","affiliation":[{"name":"Proteomics and Modomics Experimental Core Facility (PROMEC), NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Krogh","family":"S\u00f8gaard","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-4223","authenticated-orcid":false,"given":"Tiffany","family":"Khong","sequence":"additional","affiliation":[{"name":"Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia"},{"name":"Department of Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6451-3919","authenticated-orcid":false,"given":"Mi","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aina","family":"Nedal","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Spencer","sequence":"additional","affiliation":[{"name":"Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Australia"},{"name":"Department of Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7851-8083","authenticated-orcid":false,"given":"Per","family":"Bruheim","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5232-1186","authenticated-orcid":false,"given":"Marit","family":"Otterlei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491 Trondheim, Norway"},{"name":"Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, NO-7006 Trondheim, Norway"},{"name":"APIM Therapeutics A\/S, R\u00e5dhusveien 12, NO-7100 Rissa, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrm3562","article-title":"Regulation of PCNA-protein interactions for genome stability","volume":"14","author":"Mailand","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1084\/jem.20092241","article-title":"Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival","volume":"207","author":"Mocek","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.cellsig.2015.03.009","article-title":"PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling","volume":"27","author":"Olaisen","year":"2015","journal-title":"Cell. Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5693","DOI":"10.4049\/jimmunol.1102267","article-title":"Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44","volume":"187","author":"Rosental","year":"2011","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"32448","DOI":"10.18632\/oncotarget.25963","article-title":"\u201cTwo hits\u2014One stone\u201d; increased efficacy of cisplatin-based therapies by targeting PCNA\u2019s role in both DNA repair and cellular signaling","volume":"9","author":"Sogaard","year":"2018","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41388-022-02579-1","article-title":"PCNA regulates primary metabolism by scaffolding metabolic enzymes","volume":"42","author":"Rost","year":"2023","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1002\/2211-5463.12442","article-title":"The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans","volume":"8","author":"Olaisen","year":"2018","journal-title":"FEBS Open Bio"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1083\/jcb.200903138","article-title":"Identification of a novel, widespread, and functionally important PCNA-binding motif","volume":"186","author":"Gilljam","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/(SICI)1521-1878(199803)20:3<195::AID-BIES2>3.0.CO;2-R","article-title":"PCNA binding through a conserved motif","volume":"20","author":"Warbrick","year":"1998","journal-title":"Bioessays"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.molcel.2016.12.020","article-title":"Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork","volume":"65","author":"Choe","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1007\/s00018-019-03150-0","article-title":"The PCNA interaction motifs revisited: Thinking outside the PIP-box","volume":"76","author":"Prestel","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.molcel.2012.05.024","article-title":"Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress","volume":"47","author":"Ciccia","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"M\u00fcller, R., Misund, K., Holien, T., Bachke, S., Gilljam, K.M., V\u00e5tsveen, T.K., R\u00f8, T.B., Bellacchio, E., Sundan, A., and Otterlei, M. (2013). Targeting Proliferating Cell Nuclear Antigen and Its Protein Interactions Induces Apoptosis in Multiple Myeloma Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070430"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7185","DOI":"10.18632\/oncotarget.27267","article-title":"Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy","volume":"10","author":"Sogaard","year":"2019","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.tranon.2014.10.005","article-title":"Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide","volume":"7","author":"Gederaas","year":"2014","journal-title":"Transl. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Raeder, S.B., Nepal, A., Bjoras, K.O., Seelinger, M., Kolve, R.S., Nedal, A., Muller, R., and Otterlei, M. (2018). APIM-Mediated REV3L(-)PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010100"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Seelinger, M., and Otterlei, M. (2020). Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA). Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030693"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41388-022-02582-6","article-title":"ATX-101, a cell-penetrating protein targeting PCNA, can be safely administered as intravenous infusion in patients and shows clinical activity in a Phase 1 study","volume":"42","author":"Lemech","year":"2023","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4292","DOI":"10.1016\/j.febslet.2010.09.021","article-title":"Proliferating cell nuclear antigen in the cytoplasm interacts with components of glycolysis and cancer","volume":"584","author":"Naryzhny","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"lmaguel, F.A., Sanchez, T.W., Ortiz-Hernandez, G.L., and Casiano, C.A. (2020). Alpha-Enolase: Emerging Tumor-Associated Antigen, Cancer Biomarker, and Oncotherapeutic Target. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.614726"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1038\/s41388-020-1172-0","article-title":"Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma","volume":"39","author":"Ray","year":"2020","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e62592","DOI":"10.7554\/eLife.62592","article-title":"A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth","volume":"10","author":"Gillis","year":"2021","journal-title":"Elife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.biopha.2019.01.028","article-title":"6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming","volume":"111","author":"Chen","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1038\/s41375-019-0561-2","article-title":"Relapsed refractory multiple myeloma: A comprehensive overview","volume":"33","author":"Bazarbachi","year":"2019","journal-title":"Leukemia"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"El Arfani, C., De Veirman, K., Maes, K., De Bruyne, E., and Menu, E. (2018). Metabolic Features of Multiple Myeloma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041200"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1038\/leu.2016.102","article-title":"Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism","volume":"30","author":"Soriano","year":"2016","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"160018","DOI":"10.1038\/sdata.2016.18","article-title":"The FAIR Guiding Principles for scientific data management and stewardship","volume":"3","author":"Wilkinson","year":"2016","journal-title":"Sci. Data"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rost, L.M., Thorfinnsdottir, L.B., Kumar, K., Fuchino, K., Langorgen, I.E., Bartosova, Z., Kristiansen, K.A., and Bruheim, P. (2020). Absolute Quantification of the Central Carbon Metabolome in Eight Commonly Applied Prokaryotic and Eukaryotic Model Systems. Metabolites, 10.","DOI":"10.3390\/metabo10020074"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.cell.2012.02.053","article-title":"Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer","volume":"149","author":"Duncan","year":"2012","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ab.2017.01.027","article-title":"On-column trypsinization allows for re-use of matrix in modified multiplexed inhibitor beads assay","volume":"523","author":"Petrovic","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1038\/nprot.2016.136","article-title":"The MaxQuant computational platform for mass spectrometry-based shotgun proteomics","volume":"11","author":"Tyanova","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100018","DOI":"10.1074\/mcp.TIR120.002216","article-title":"PTM-Shepherd: Analysis and Summarization of Post-Translational and Chemical Modifications From Open Search Results","volume":"20","author":"Geiszler","year":"2021","journal-title":"Mol. Cell. Proteom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1074\/mcp.M113.031591","article-title":"Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ","volume":"13","author":"Cox","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_34","first-page":"1227","article-title":"Nonparametric statistical inferences","volume":"55","author":"Chakraborti","year":"2014","journal-title":"Stat. Pap."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The PRIDE database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Csordas","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11752","DOI":"10.18632\/oncotarget.24357","article-title":"APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer","volume":"9","author":"Sogaard","year":"2018","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rost, L.M., Shafaei, A., Fuchino, K., and Bruheim, P. (2020). Zwitterionic HILIC tandem mass spectrometry with isotope dilution for rapid, sensitive and robust quantification of pyridine nucleotides in biological extracts. J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 1144.","DOI":"10.1016\/j.jchromb.2020.122078"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1038\/nprot.2013.095","article-title":"Analysis of GSH and GSSG after derivatization with N-ethylmaleimide","volume":"8","author":"Giustarini","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Herzog, K., IJlst, L., van Cruchten, A.G., van Roermund, C.W.T., Kulik, W., Wanders, R.J.A., and Waterham, H.R. (2019). An UPLC-MS\/MS Assay to Measure Glutathione as Marker for Oxidative Stress in Cultured Cells. Metabolites, 9.","DOI":"10.3390\/metabo9030045"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sun, X., Berger, S., Heinrich, P., Marchiq, I., Pouyssegur, J., Renner, K., Oefner, P.J., and Dettmer, K. (2020). Optimized Protocol for the In Situ Derivatization of Glutathione with N-Ethylmaleimide in Cultured Cells and the Simultaneous Determination of Glutathione\/Glutathione Disulfide Ratio by HPLC-UV-QTOF-MS. Metabolites, 10.","DOI":"10.3390\/metabo10070292"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tomin, T., Schittmayer, M., and Birner-Gruenberger, R. (2020). Addressing Glutathione Redox Status in Clinical Samples by Two-Step Alkylation with N-ethylmaleimide Isotopologues. Metabolites, 10.","DOI":"10.3390\/metabo10020071"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13045-015-0117-5","article-title":"Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K\/AKT pathway","volume":"8","author":"Fu","year":"2015","journal-title":"J. Hematol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Al-Odat, O., von Suskil, M., Chitren, R., Elbezanti, W., Srivastava, S., Budak-Alpddogan, T., Jonnalagadda, S., Aggarwal, B., and Pandey, M. (2021). Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.699629"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/j.1600-0609.2009.01225.x","article-title":"High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis","volume":"82","author":"Brenne","year":"2009","journal-title":"Eur. J. Haematol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Uva, P., Lahm, A., Sbardellati, A., Grigoriadis, A., Tutt, A., and de Rinaldis, E. (2010). Comparative Membranome expression analysis in primary tumors and derived cell lines. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011742"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"R\u00f8st, L.M., Olaisen, C., Sharma, A., Nedal, A., Petrovic, V., Kvitvang, H.F.N., Bruheim, P., and Otterlei, M. (2020). PCNA has specific functions in regulation of metabolism in haematological cells. bioRxiv.","DOI":"10.1101\/2020.04.29.067512"},{"key":"ref_49","first-page":"1541","article-title":"Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor\/phosphatidylinositol 3-kinase\/PTEN\/AKT\/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics","volume":"60","author":"Zhong","year":"2000","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.canlet.2019.07.018","article-title":"The Ig superfamily protein PTGFRN coordinates survival signaling in glioblastoma multiforme","volume":"462","author":"Aguila","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Gottschalk, B., Koshenov, Z., Bachkoenig, O.A., Rost, R., Malli, R., and Graier, W.F. (2022). MFN2 mediates ER-mitochondrial coupling during ER stress through specialized stable contact sites. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.918691"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113376","DOI":"10.1016\/j.yexcr.2022.113376","article-title":"IRE1alpha-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells","volume":"421","author":"Mao","year":"2022","journal-title":"Exp. Cell Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s42255-023-00781-3","article-title":"The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells","volume":"5","author":"Talwar","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Gravina, G.L., Colapietro, A., Mancini, A., Rossetti, A., Martellucci, S., Ventura, L., Di Franco, M., Marampon, F., Mattei, V., and Biordi, L.A. (2022). ATX-101, a Peptide Targeting PCNA, Has Antitumor Efficacy Alone or in Combination with Radiotherapy in Murine Models of Human Glioblastoma. Cancers, 14.","DOI":"10.3390\/cancers14020289"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"108831","DOI":"10.1016\/j.celrep.2021.108831","article-title":"Blockade of 6-phosphogluconate dehydrogenase generates CD8(+) effector T cells with enhanced anti-tumor function","volume":"34","author":"Daneshmandi","year":"2021","journal-title":"Cell Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature11331","article-title":"Passenger deletions generate therapeutic vulnerabilities in cancer","volume":"488","author":"Muller","year":"2012","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"944","DOI":"10.2741\/4526","article-title":"Alpha-Enolase (ENO1), a potential target in novel immunotherapies","volume":"22","author":"Cappello","year":"2017","journal-title":"Front. Biosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13787","DOI":"10.1073\/pnas.1203339109","article-title":"MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer","volume":"109","author":"Chaika","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/cam4.4911","article-title":"Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK","volume":"12","author":"Chen","year":"2023","journal-title":"Cancer Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jcb.29869","article-title":"AML poor prognosis factor, TPD52, is associated with the maintenance of haematopoietic stem cells through regulation of cell proliferation","volume":"122","author":"Kang","year":"2021","journal-title":"J. Cell. Biochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2040620721989585","DOI":"10.1177\/2040620721989585","article-title":"B-cell maturation antigen (BCMA) in multiple myeloma: The new frontier of targeted therapies","volume":"12","author":"Sanchez","year":"2021","journal-title":"Ther. Adv. Hematol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Simmons, G.L., and Castaneda Puglianini, O. (2022). T-Cell-Based Cellular Immunotherapy of Multiple Myeloma: Current Developments. Cancers, 14.","DOI":"10.3390\/cancers14174249"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e20201811","DOI":"10.1084\/jem.20201811","article-title":"LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy","volume":"218","author":"Sharma","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/intimm\/dxab028","article-title":"Blockade of checkpoint ILT3\/LILRB4\/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB\/Yaa mice","volume":"33","author":"Su","year":"2021","journal-title":"Int. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/ni1047","article-title":"Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins","volume":"5","author":"Heissmeyer","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13046-022-02351-z","article-title":"Mouse mesenchymal stem cell-derived exosomal miR-466f-3p reverses EMT process through inhibiting AKT\/GSK3beta pathway via c-MET in radiation-induced lung injury","volume":"41","author":"Li","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1007\/s12035-020-02231-7","article-title":"TSG101 Promotes the Proliferation, Migration, and Invasion of Human Glioma Cells by Regulating the AKT\/GSK3beta\/beta-Catenin and RhoC\/Cofilin Pathways","volume":"58","author":"Zhu","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e110372","DOI":"10.15252\/embj.2021110372","article-title":"TSG101 associates with PARP1 and is essential for PARylation and DNA damage-induced NF-kappaB activation","volume":"41","author":"Tufan","year":"2022","journal-title":"EMBO J."},{"key":"ref_70","first-page":"4011","article-title":"The role of ZNRF2 in the growth of non-small cell lung cancer","volume":"20","author":"Zhang","year":"2016","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.tjog.2022.04.005","article-title":"Uncovering of potential molecular markers for cervical squamous cell carcinoma (CESC) based on analysis of methylated-differentially expressed genes","volume":"61","author":"Liu","year":"2022","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"737","DOI":"10.21037\/atm.2019.11.122","article-title":"DNA methylation-based prognostic biomarkers of acute myeloid leukemia patients","volume":"7","author":"Hu","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"596899","DOI":"10.3389\/pore.2021.596899","article-title":"Identification of DNA-Repair-Related Five-Gene Signature to Predict Prognosis in Patients with Esophageal Cancer","volume":"27","author":"Wang","year":"2021","journal-title":"Pathol. Oncol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12935-021-01779-1","article-title":"Identification of DNA repair-related genes predicting pathogenesis and prognosis for liver cancer","volume":"21","author":"Zhu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Xu, J., Ma, H., and Shan, B. (2022). Up-Frameshift Suppressor 3 as a prognostic biomarker and correlated with immune infiltrates: A pan-cancer analysis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0273163"},{"key":"ref_76","first-page":"4098","article-title":"Multifaceted regulation and functions of fatty acid desaturase 2 in human cancers","volume":"10","author":"Li","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Wu, L., Hu, X., Dai, H., Chen, K., and Liu, B. (2021). Identification of an m6A Regulators-Mediated Prognosis Signature For Survival Prediction and Its Relevance to Immune Infiltration in Melanoma. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.718912"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/ijc.33988","article-title":"Identification of novel prostate cancer genes in patients stratified by Gleason classification: Role of antitumoral genes","volume":"151","author":"Zwir","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/2211-5463.13524","article-title":"Identification of genes contributing to cisplatin resistance in osteosarcoma cells","volume":"13","author":"Xie","year":"2023","journal-title":"FEBS Open Bio"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Chen, A., Jing, W., Qiu, J., and Zhang, R. (2022). Prediction of Cervical Cancer Outcome by Identifying and Validating a NAD+ Metabolism-Derived Gene Signature. J. Pers. Med., 12.","DOI":"10.3390\/jpm12122031"},{"key":"ref_81","first-page":"4570235","article-title":"Abnormal Expression and Prognosis Value of COG Complex Members in Kidney Renal Clear Cell Carcinoma (KIRC)","volume":"2021","author":"Zhang","year":"2021","journal-title":"Dis. Markers"},{"key":"ref_82","first-page":"4451178","article-title":"The Antitumor Effect of TPD52L2 Silencing on Oxaliplatin-Resistant Gastric Carcinoma Is Related to Endoplasmic Reticulum Stress In Vitro","volume":"2022","author":"Zhang","year":"2022","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"107982","DOI":"10.1016\/j.celrep.2020.107982","article-title":"Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-kappaB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells","volume":"32","author":"Cornelis","year":"2020","journal-title":"Cell Rep."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kaul, Z., Mookherjee, D., Das, S., Chatterjee, D., Chakrabarti, S., and Chakrabarti, O. (2020). Loss of tumor susceptibility gene 101 (TSG101) perturbs endoplasmic reticulum structure and function. Biochim. Biophys. Acta Mol. Cell Res., 1867.","DOI":"10.1016\/j.bbamcr.2020.118741"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1128\/JVI.02363-14","article-title":"Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis","volume":"89","author":"Teng","year":"2015","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ymgme.2012.09.011","article-title":"Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease","volume":"107","author":"Nishiyama","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/bjh.15210","article-title":"Resistance to proteasome inhibitors and other targeted therapies in myeloma","volume":"182","author":"Kuss","year":"2018","journal-title":"Br. J. Haematol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/23\/3963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:39:49Z","timestamp":1760114389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/23\/3963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":87,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["cancers16233963"],"URL":"https:\/\/doi.org\/10.3390\/cancers16233963","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,26]]}}}