CIGB-300 internalizes and impairs viability of NSCLC cells lacking actionable targets by inhibiting casein kinase-2 signaling.
Casein Kinase II
/ antagonists & inhibitors
Humans
Carcinoma, Non-Small-Cell Lung
/ pathology
Lung Neoplasms
/ pathology
Animals
Signal Transduction
/ drug effects
Cell Line, Tumor
Mice
Cell Survival
/ drug effects
Cell Proliferation
/ drug effects
Xenograft Model Antitumor Assays
Protein Kinase Inhibitors
/ pharmacology
Antineoplastic Agents
/ pharmacology
Phosphorylation
/ drug effects
A549 Cells
Peptides, Cyclic
CK2
CPP-based drug
NSCLC
Peptide inhibitor
Protein kinase
Target therapy
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 10 2024
29 10 2024
Historique:
received:
17
06
2024
accepted:
09
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Overall response rates in advanced Non-Small Cell Lung Cancer (NSCLC) remains low. Thus, novel molecular targets, tailored drugs and/or drug combinations are needed. Casein Kinase-2 (CK2) is a constitutively active and frequently over-expressed enzyme which fosters tumor survival, proliferation and metastasis. By using a clinical-grade and Cell Penetrating Peptide-based inhibitor coined as CIGB-300, we explore the anti-neoplastic effects caused by interruption of CK2 signaling in lung cancer cells lacking EGFR, ALK and ROS mutations. CIGB-300 penetrated and impaired viability and proliferation of Lung Adenocarcinoma (LUAD) (A549, NCI-H522) and Lung Squamous Carcinoma (LUSC) (NCI-H226 and SK-MES-1) cells in a dose-response manner. The differential activity could not be explained by overall peptide uptake or its subcellular distribution, as evidenced by flow cytometry and confocal microscopy. Upon internalization, CIGB-300 interacted with CK2 catalytic subunits (ɑ1/ɑ2) and CK2 substrates, thus impairing phosphorylation of enzyme substrates (CDC37s13, NPM1s125) and downstream proteins (RPS6s325/326). CK2 inhibition induced an early Reactive Oxygen Species (ROS) and mitochondrial membrane depolarization, which predates lung cancer cell death. Finally, intravenous injection of CIGB-300 in a cell line-based xenograft corroborated CIGB-300's anti-tumor effects and suggested concurrent in situ reductions of CSNK2ɑ subunit and downstream RPS6s235/236 phosphorylation. Overall, CIGB-300 therapeutic hypothesis and antineoplastic effects demonstrated herein, further support the evaluation of this clinical-grade CK2 inhibitor in advanced NSCLC with limited therapeutic options.
Identifiants
pubmed: 39472715
doi: 10.1038/s41598-024-75990-1
pii: 10.1038/s41598-024-75990-1
doi:
Substances chimiques
Casein Kinase II
EC 2.7.11.1
CIGB-300
X6HMT2EDH9
Protein Kinase Inhibitors
0
Antineoplastic Agents
0
Peptides, Cyclic
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26038Subventions
Organisme : This research was supported by the "National key R&D program of China 2021YFE0192100"
ID : 2021YFE0192100
Organisme : This research was supported by the "National key R&D program of China 2021YFE0192100"
ID : 2021YFE0192100
Organisme : This research was supported by the "National key R&D program of China 2021YFE0192100"
ID : 2021YFE0192100
Informations de copyright
© 2024. The Author(s).
Références
Wang, M., Herbst, R. S. & Boshoff, C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat. Med. 27, 1345–1356 (2021).
doi: 10.1038/s41591-021-01450-2
Dang, C. V., Reddy, E. P., Shokat, K. M. & Soucek, L. Drugging the ‘undruggable’ cancer targets. Nat. Rev. Cancer 17, 502–508 (2017).
doi: 10.1038/nrc.2017.36
Lipinski, K. A. et al. Cancer evolution and the limits of predictability in precision cancer medicine. Trends Cancer 2, 49–63 (2016).
doi: 10.1016/j.trecan.2015.11.003
Rivera-Concepcion, J., Uprety, D. & Adjei, A. A. Challenges in the use of targeted therapies in non-small cell lung cancer. Cancer Res. Treat. 54, 315–329 (2022).
doi: 10.4143/crt.2022.078
Pirker, R. Chemotherapy remains a cornerstone in the treatment of nonsmall cell lung cancer. Curr. Opin. Oncol. 32, 63–67 (2020).
doi: 10.1097/CCO.0000000000000592
Ortega, C. E., Seidner, Y. & Dominguez, I. Mining CK2 in cancer. PLoS One 9, e115609 (2014).
doi: 10.1371/journal.pone.0115609
Chua, M. M. J. et al. CK2 in cancer: Cellular and biochemical mechanisms and potential therapeutic target. Pharmaceuticals (Basel). 10 (2017).
Litchfield, D. W. Protein kinase CK2: Structure, regulation and role in cellular decisions of life and death. Biochem. J. 369, 1–15 (2003).
doi: 10.1042/bj20021469
Turowec, J. P., Vilk, G., Gabriel, M. & Litchfield, D. W. Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2α’: Implications for pathological roles of CK2 in promoting cancer cell survival. Oncotarget 4, 560–571 (2013).
doi: 10.18632/oncotarget.948
Deshiere, A. et al. Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction. Oncogene 32, 1373–1383 (2013).
doi: 10.1038/onc.2012.165
Yaylim, I. & Isbir, T. Enhanced casein kinase II (CK II) activity in human lung tumours. Anticancer Res. 22, 215–218 (2002).
Li, Q. et al. Association of protein kinase CK2 inhibition with cellular radiosensitivity of non-small cell lung cancer. Sci. Rep. 7, 16134 (2017).
doi: 10.1038/s41598-017-16012-1
Liu, Y. et al. CK2α’ drives lung cancer metastasis by targeting BRMS1 nuclear export and degradation. Cancer Res. 76, 2675–2686 (2016).
doi: 10.1158/0008-5472.CAN-15-2888
Iegre, J. et al. Chemical probes targeting the kinase CK2: A journey outside the catalytic box. Org. Biomol. Chem. 19, 4380–4396 (2021).
doi: 10.1039/D1OB00257K
Solares, A. M. et al. Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer 9, 146 (2009).
doi: 10.1186/1471-2407-9-146
Siddiqui-Jain, A. et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 70, 10288–10298 (2010).
doi: 10.1158/0008-5472.CAN-10-1893
Perea, S. E. et al. Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cancer Res. 64, 7127–7129 (2004).
doi: 10.1158/0008-5472.CAN-04-2086
Perera, Y. et al. Systemic administration of a peptide that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int. J. cancer 122, 57–62 (2008).
doi: 10.1002/ijc.23013
Gottardo, M. F. et al. Preclinical efficacy of CIGB-300, an anti-CK2 peptide, on breast cancer metastasic colonization. Sci. Rep. 10, 14689 (2020).
doi: 10.1038/s41598-020-71854-6
Perera, Y. et al. Clinical-grade peptide-based inhibition of CK2 blocks viability and proliferation of T-ALL cells and counteracts IL-7 stimulation and stromal support. Cancers (Basel). 12 (2020).
Martins, L. R. et al. Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specific cell-permeable peptide inhibitor. Oncotarget 5, 258–263 (2014).
doi: 10.18632/oncotarget.1513
Rosales, M. et al. Targeting of protein kinase CK2 in acute myeloid leukemia cells using the clinical-grade synthetic-peptide CIGB-300. Biomedicines. 9 (2021).
Perera, Y. et al. CIGB-300 anticancer peptide regulates the protein kinase CK2-dependent phosphoproteome. Mol. Cell. Biochem. 470, 63–75 (2020).
doi: 10.1007/s11010-020-03747-1
Pérez, G. V et al. CIGB-300 anticancer peptide differentially interacts with CK2 subunits and regulates specific signaling mediators in a highly sensitive large cell lung carcinoma cell model. Biomedicines. 11 (2022).
Farina, H. G. et al. CIGB-300, a proapoptotic peptide, inhibits angiogenesis in vitro and in vivo. Exp. Cell Res. 317, 1677–1688 (2011).
doi: 10.1016/j.yexcr.2011.04.011
Benavent Acero, F. et al. CIGB-300, an anti-CK2 peptide, inhibits angiogenesis, tumor cell invasion and metastasis in lung cancer models. Lung Cancer 107, 14–21 (2017).
doi: 10.1016/j.lungcan.2016.05.026
Benavent Acero, F. R. et al. Mechanisms of cellular uptake, intracellular transportation, and degradation of CIGB-300, a Tat-conjugated peptide, in tumor cell lines. Mol. Pharm. 11, 1798–1807 (2014).
doi: 10.1021/mp4006062
Gazdar, A. F., Girard, L., Lockwood, W. W., Lam, W. L. & Minna, J. D. Lung cancer cell lines as tools for biomedical discovery and research. J. Natl. Cancer Inst. 102, 1310–1321 (2010).
doi: 10.1093/jnci/djq279
Perera, Y. et al. Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis. Mol. Cell. Biochem. 404, 103–112 (2015).
doi: 10.1007/s11010-015-2370-x
Vázquez-Blomquist, D. et al. Gene expression profiling unveils the temporal dynamics of CIGB-300-regulated transcriptome in AML cell lines. BMC Genomics 24, 373 (2023).
doi: 10.1186/s12864-023-09472-5
Perera, Y. et al. Sensitivity of tumor cells towards CIGB-300 anticancer peptide relies on its nucleolar localization. J. Pept. Sci. Off Publ. Eur. Pept. Soc. 18, 215–223 (2012).
Rosales, M. et al. CIGB-300-regulated proteome reveals common and tailored response patterns of AML cells to CK2 inhibition. Front. Mol. Biosci. 9, 834814 (2022).
doi: 10.3389/fmolb.2022.834814
Sondka, Z. et al. COSMIC: A curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210–D1217 (2024).
doi: 10.1093/nar/gkad986
Barretina, J. et al. The cancer cell line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
doi: 10.1038/nature11003
Reissmann, S. Cell penetration: Scope and limitations by the application of cell-penetrating peptides. J. Pept. Sci. Off Publ. Eur. Pept. Soc. 20, 760–784 (2014).
Skotland, T., Iversen, T. G., Torgersen, M. L. & Sandvig, K. Cell-penetrating peptides: Possibilities and challenges for drug delivery in vitro and in vivo. Molecules 20, 13313–13323 (2015).
doi: 10.3390/molecules200713313
Stauber, R. H. & Pavlakis, G. N. Intracellular trafficking and interactions of the HIV-1 Tat protein. Virology 252, 126–136 (1998).
doi: 10.1006/viro.1998.9400
Ruseska, I. & Zimmer, A. Internalization mechanisms of cell-penetrating peptides. Beilstein J. Nanotechnol. 11, 101–123 (2020).
doi: 10.3762/bjnano.11.10
Zhou, Y., Du, W., Koretsky, T., Bagby, G. C. & Pang, Q. TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice. Blood 112, 2474–2483 (2008).
doi: 10.1182/blood-2007-12-130211
Borgo, C. et al. Generation and quantitative proteomics analysis of CK2α/α’((-/-)) cells. Sci. Rep. 7, 42409 (2017).
doi: 10.1038/srep42409
Qaiser, F. et al. Protein kinase CK2 inhibition induces cell death via early impact on mitochondrial function. J. Cell. Biochem. 115, 2103–2115 (2014).
doi: 10.1002/jcb.24887
Yang, B., Yao, J., Li, B., Shao, G. & Cui, Y. Inhibition of protein kinase CK2 sensitizes non-small cell lung cancer cells to cisplatin via upregulation of PML. Mol. Cell. Biochem. 436, 87–97 (2017).
doi: 10.1007/s11010-017-3081-2
Bliesath, J. et al. Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Lett. 322, 113–118 (2012).
doi: 10.1016/j.canlet.2012.02.032
So, K. S. et al. AKT/mTOR down-regulation by CX-4945, a CK2 inhibitor, promotes apoptosis in chemorefractory non-small cell lung cancer cells. Anticancer Res. 35, 1537–1542 (2015).
Rodríguez-Ulloa, A. et al. Proteomic profile regulated by the anticancer peptide CIGB-300 in non-small cell lung cancer (NSCLC) cells. J. Proteome Res. 9, 5473–5483 (2010).
doi: 10.1021/pr100728v
Perera, Y. et al. Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity. Mol. Cancer Ther. 8, 1189–1196 (2009).
doi: 10.1158/1535-7163.MCT-08-1056
Firnau, M.-B. & Brieger, A. CK2 and the hallmarks of cancer. Biomedicines. 10 (2022).
D’Amore, C., Borgo, C., Sarno, S. & Salvi, M. Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy - potential clinical relevance. Cell. Oncol. (Dordr) 43, 1003–1016 (2020).
doi: 10.1007/s13402-020-00566-w
Gou, Q. et al. Inhibition of CK2/ING4 pathway facilitates non-small cell lung cancer immunotherapy. Adv. Sci. 10 e2304068 (Weinheim, Baden-Wurttemberg, Ger., 2023).