Targeting the Cyclin-dependent Kinase 5 in Metastatic Melanoma

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Mar 21

PMID 32193336

Citations 13

Authors

Samanta Sharma

Tian Zhang

Wojciech Michowski

Vito W Rebecca

Min Xiao

Roberta Ferretti

Jan M Suski

Roderick T Bronson

Joao A Paulo

Dennie Frederick

Anne Fassl

Genevieve M Boland

Yan Geng

Jacqueline A Lees

Rene H Medema

Meenhard Herlyn

Steven P Gygi

Piotr Sicinski

Affiliations

Soon will be listed here.

Abstract

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

Citing Articles

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CDK5: an oncogene or an anti-oncogene: location location location.

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Cdk5 activation promotes Cos-7 cells transition towards neuronal-like cells.

Bao L, Lan X, Zhang G, Bao X, Li B, Ma D Transl Neurosci. 2023; 14(1):20220318.

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Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice.

Kruger B, Steppe L, Vettorazzi S, Haffner-Luntzer M, Lee S, Dorn A Biomedicines. 2022; 10(2).

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References

Wei K, Ye Z, Li Z, Dang Y, Chen X, Huang N . An immunohistochemical study of cyclin-dependent kinase 5 (CDK5) expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): a possible prognostic biomarker. World J Surg Oncol. 2016; 14(1):34. PMC: 4746778. DOI: 10.1186/s12957-016-0787-7. View

Strock C, Park J, Nakakura E, Bova G, Isaacs J, Ball D . Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006; 66(15):7509-15. DOI: 10.1158/0008-5472.CAN-05-3048. View

Nieminen M, Henttinen T, Merinen M, Marttila-Ichihara F, Eriksson J, Jalkanen S . Vimentin function in lymphocyte adhesion and transcellular migration. Nat Cell Biol. 2006; 8(2):156-62. DOI: 10.1038/ncb1355. View

Garman B, Anastopoulos I, Krepler C, Brafford P, Sproesser K, Jiang Y . Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. Cell Rep. 2017; 21(7):1936-1952. PMC: 5709812. DOI: 10.1016/j.celrep.2017.10.052. View

Kawauchi T . Cdk5 regulates multiple cellular events in neural development, function and disease. Dev Growth Differ. 2014; 56(5):335-48. DOI: 10.1111/dgd.12138. View

Bishop A, Ubersax J, Petsch D, Matheos D, Gray N, Blethrow J . A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature. 2000; 407(6802):395-401. DOI: 10.1038/35030148. View

Bisht S, Nolting J, Schutte U, Haarmann J, Jain P, Shah D . Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread-Identification of a Promising Novel therapeutic target. Transl Oncol. 2015; 8(4):295-307. PMC: 4562979. DOI: 10.1016/j.tranon.2015.06.002. View

Inagaki M, Gonda Y, Matsuyama M, Nishizawa K, Nishi Y, Sato C . Intermediate filament reconstitution in vitro. The role of phosphorylation on the assembly-disassembly of desmin. J Biol Chem. 1988; 263(12):5970-8. View

Gray-Schopfer V, da Rocha Dias S, Marais R . The role of B-RAF in melanoma. Cancer Metastasis Rev. 2005; 24(1):165-83. DOI: 10.1007/s10555-005-5865-1. View

10.

Dorand R, Nthale J, Myers J, Barkauskas D, Avril S, Chirieleison S . Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science. 2016; 353(6297):399-403. PMC: 5051664. DOI: 10.1126/science.aae0477. View

11.

Rodriguez M, Peralta-Leal A, OValle F, Rodriguez-Vargas J, Gonzalez-Flores A, Majuelos-Melguizo J . PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genet. 2013; 9(6):e1003531. PMC: 3681683. DOI: 10.1371/journal.pgen.1003531. View

12.

Eggers J, Grandgenett P, Collisson E, Lewallen M, Tremayne J, Singh P . Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. Clin Cancer Res. 2011; 17(19):6140-50. PMC: 3425449. DOI: 10.1158/1078-0432.CCR-10-2288. View

13.

Malumbres M, Barbacid M . Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9(3):153-66. DOI: 10.1038/nrc2602. View

14.

Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V . The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013; 24(4):499-511. PMC: 3849320. DOI: 10.1016/j.ccr.2013.08.027. View

15.

Lockwood W, Chari R, Coe B, Girard L, MacAulay C, Lam S . DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene. 2008; 27(33):4615-24. PMC: 2849646. DOI: 10.1038/onc.2008.98. View

16.

Tripathi B, Qian X, Mertins P, Wang D, Papageorge A, Carr S . CDK5 is a major regulator of the tumor suppressor DLC1. J Cell Biol. 2014; 207(5):627-42. PMC: 4259810. DOI: 10.1083/jcb.201405105. View

17.

Lavoie J, LAllemain G, Brunet A, Muller R, Pouyssegur J . Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996; 271(34):20608-16. DOI: 10.1074/jbc.271.34.20608. View

18.

Liu J, Wang X, Huang B, Zhu F, Zhang R, Wu G . Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. 2010; 28(3):673-8. DOI: 10.1007/s12032-010-9510-7. View

19.

Wuhr M, Haas W, McAlister G, Peshkin L, Rad R, Kirschner M . Accurate multiplexed proteomics at the MS2 level using the complement reporter ion cluster. Anal Chem. 2012; 84(21):9214-21. PMC: 3771681. DOI: 10.1021/ac301962s. View

20.

Samuels B, Hsueh Y, Shu T, Liang H, Tseng H, Hong C . Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron. 2007; 56(5):823-37. PMC: 2151975. DOI: 10.1016/j.neuron.2007.09.035. View