Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function.
Breast cancer
Death-associated protein kinase 1 (DAPK1)
Mouse double minute 2 (MDM2)
Tumor suppressor
Tumorigenesis
p53
Journal
Archives of pharmacal research
ISSN: 1976-3786
Titre abrégé: Arch Pharm Res
Pays: Korea (South)
ID NLM: 8000036
Informations de publication
Date de publication:
07 Oct 2023
07 Oct 2023
Historique:
received:
15
03
2023
accepted:
28
09
2023
medline:
7
10
2023
pubmed:
7
10
2023
entrez:
7
10
2023
Statut:
aheadofprint
Résumé
Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2 and phosphorylates it at Thr419. DAPK1-mediated MDM2 phosphorylation promoted its protein degradation via the ubiquitin-proteasome pathway, resulting in upregulated p53 expression. DAPK1 overexpression, but not its kinase activity-deficient form, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown produced the opposite effects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression significantly reduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic effect. Finally, DAPK1 expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest that DAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function in breast cancer.
Identifiants
pubmed: 37804415
doi: 10.1007/s12272-023-01469-8
pii: 10.1007/s12272-023-01469-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Natural Science Foundation of China
ID : 81970993
Organisme : National Natural Science Foundation of China
ID : 82271449
Informations de copyright
© 2023. The Pharmaceutical Society of Korea.
Références
Bialik S, Kimchi A (2006) The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 75:189–210. https://doi.org/10.1146/annurev.biochem.75.103004.142615
doi: 10.1146/annurev.biochem.75.103004.142615
pubmed: 16756490
Chen HY, Lee YR, Chen RH (2014) The functions and regulations of DAPK in cancer metastasis. Apoptosis 19(2):364–370. https://doi.org/10.1007/s10495-013-0923-6
doi: 10.1007/s10495-013-0923-6
pubmed: 24166138
Chen D, Zhou XZ, Lee TH (2019) Death-associated protein kinase 1 as a promising drug target in cancer and Alzheimer’s disease. Recent Pat Anticancer Drug Discov 14(2):144–157. https://doi.org/10.2174/1574892814666181218170257
doi: 10.2174/1574892814666181218170257
pubmed: 30569876
pmcid: 6751350
Chen D, Mei Y, Kim N, Lan G, Gan CL, Fan F, Zhang T, Xia Y, Wang L, Lin C, Ke F, Zhou XZ, Lu KP, Lee TH (2020) Melatonin directly binds and inhibits death-associated protein kinase 1 function in Alzheimer’s disease. J Pineal Res 69(2):e12665. https://doi.org/10.1111/jpi.12665
doi: 10.1111/jpi.12665
pubmed: 32358852
pmcid: 7890046
Chen D, Lan G, Li R, Mei Y, Shui X, Gu X, Wang L, Zhang T, Gan CL, Xia Y, Hu L, Tian Y, Zhang M, Lee TH (2022) Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer’s disease. Transl Neurodegener 11(1):27. https://doi.org/10.1186/s40035-022-00302-4
doi: 10.1186/s40035-022-00302-4
pubmed: 35527277
pmcid: 9082841
Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J (2011) Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage. Mol Cell Biol 31(24):4951–4963. https://doi.org/10.1128/MCB.05553-11
doi: 10.1128/MCB.05553-11
pubmed: 21986495
pmcid: 3233024
Chou SE, Huang CY, Sheen-Chen SM, Liu YW, Tsai CH, Lin YH, Huang CC, Tang RP (2011) An evaluation of prognostic value of death-associated protein kinase 1 in breast cancer. Anticancer Res 31(10):3633–3636
pubmed: 21965790
Craig AL, Chrystal JA, Fraser JA, Sphyris N, Lin Y, Harrison BJ, Scott MT, Dornreiter I, Hupp TR (2007) The MDM2 ubiquitination signal in the DNA-binding domain of p53 forms a docking site for calcium calmodulin kinase superfamily members. Mol Cell Biol 27(9):3542–3555. https://doi.org/10.1128/MCB.01595-06
doi: 10.1128/MCB.01595-06
pubmed: 17339337
pmcid: 1899961
Dai Z, Wang X, Peng R, Zhang B, Han Q, Lin J, Wang J, Lin J, Jiang M, Liu H, Lee TH, Lu KP, Zheng M (2022) Induction of IL-6Ralpha by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma. Cancer Lett 524:161–171. https://doi.org/10.1016/j.canlet.2021.10.024
doi: 10.1016/j.canlet.2021.10.024
pubmed: 34687791
Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A (1995) Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 9(1):15–30. https://doi.org/10.1101/gad.9.1.15
doi: 10.1101/gad.9.1.15
pubmed: 7828849
den Brok WD, Speers CH, Gondara L, Baxter E, Tyldesley SK, Lohrisch CA (2017) Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. Breast Cancer Res Treat 161(3):549–556. https://doi.org/10.1007/s10549-016-4080-9
doi: 10.1007/s10549-016-4080-9
Ghalkhani E, Akbari MT, Izadi P, Mahmoodzadeh H, Kamali F (2021) Assessment of DAPK1 and CAVIN3 gene promoter methylation in breast invasive ductal carcinoma and metastasis. Cell J 23(4):397–405. https://doi.org/10.22074/cellj.2021.7251
doi: 10.22074/cellj.2021.7251
pubmed: 34455714
pmcid: 8405083
Haupt S, Vijayakumaran R, Miranda PJ, Burgess A, Lim E, Haupt Y (2017) The role of MDM2 and MDM4 in breast cancer development and prevention. J Mol Cell Biol 9(1):53–61. https://doi.org/10.1093/jmcb/mjx007
doi: 10.1093/jmcb/mjx007
pubmed: 28096293
pmcid: 5439375
Huang Y, Wang C, Li K, Ye Y, Shen A, Guo L, Chen P, Meng C, Wang Q, Yang X, Huang Z, Xing X, Lin Y, Liu X, Peng J, Lin Y (2020) Death-associated protein kinase 1 suppresses hepatocellular carcinoma cell migration and invasion by upregulation of DEAD-box helicase 20. Cancer Sci 111(8):2803–2813. https://doi.org/10.1111/cas.14499
doi: 10.1111/cas.14499
pubmed: 32449268
pmcid: 7419049
Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L, Kimchi A (1997) DAP kinase links the control of apoptosis to metastasis. Nature 390(6656):180–184. https://doi.org/10.1038/36599
doi: 10.1038/36599
pubmed: 9367156
International Agency for Research on Cancer (IFAR); WHO. Globocan 2020. Available online https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf
Karni-Schmidt O, Lokshin M, Prives C (2016) The roles of MDM2 and MDMX in cancer. Annu Rev Pathol 11:617–644. https://doi.org/10.1146/annurev-pathol-012414-040349
doi: 10.1146/annurev-pathol-012414-040349
pubmed: 27022975
pmcid: 6028239
Kim N, Chen D, Zhou XZ, Lee TH (2019) Death-associated protein kinase 1 phosphorylation in neuronal cell death and neurodegenerative disease. Int J Mol Sci. https://doi.org/10.3390/ijms20133131
doi: 10.3390/ijms20133131
pubmed: 31906195
pmcid: 6981941
Kim J, Choi KW, Lee J, Lee J, Lee S, Sun R, Kim J (2021) Wnt/beta-catenin signaling inhibitors suppress the tumor-initiating properties of a CD44(+)CD133(+) subpopulation of Caco-2 cells. Int J Biol Sci 17(7):1644–1659. https://doi.org/10.7150/ijbs.58612
doi: 10.7150/ijbs.58612
pubmed: 33994850
pmcid: 8120464
Kim J, Lee S, Sun R, Kim J (2022) Juglone and KPT6566 suppress the tumorigenic potential of CD44(+)CD133(+) tumor-initiating Caco-2 cells in vitro and in vivo. Front Cell Dev Biol 10:861045. https://doi.org/10.3389/fcell.2022.861045
doi: 10.3389/fcell.2022.861045
pubmed: 35433695
pmcid: 9006057
Kissil JL, Feinstein E, Cohen O, Jones PA, Tsai YC, Knowles MA, Eydmann ME, Kimchi A (1997) DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene 15(4):403–407. https://doi.org/10.1038/sj.onc.1201172
doi: 10.1038/sj.onc.1201172
pubmed: 9242376
Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP (2011) Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell 42(2):147–159. https://doi.org/10.1016/j.molcel.2011.03.005
doi: 10.1016/j.molcel.2011.03.005
pubmed: 21497122
pmcid: 3088080
Lehmann U, Celikkaya G, Hasemeier B, Langer F, Kreipe H (2002) Promoter hypermethylation of the death-associated protein kinase gene in breast cancer is associated with the invasive lobular subtype. Cancer Res 62(22):6634–6638
pubmed: 12438260
Levine AJ (2020) p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer 20(8):471–480. https://doi.org/10.1038/s41568-020-0262-1
doi: 10.1038/s41568-020-0262-1
pubmed: 32404993
Levy D, Plu-Bureau G, Decroix Y, Hugol D, Rostene W, Kimchi A, Gompel A (2004) Death-associated protein kinase loss of expression is a new marker for breast cancer prognosis. Clin Cancer Res 10(9):3124–3130. https://doi.org/10.1158/1078-0432.ccr-03-0213
doi: 10.1158/1078-0432.ccr-03-0213
pubmed: 15131053
Li J, Kurokawa M (2015) Regulation of MDM2 stability after DNA damage. J Cell Physiol 230(10):2318–2327. https://doi.org/10.1002/jcp.24994
doi: 10.1002/jcp.24994
pubmed: 25808808
pmcid: 5810548
Li L, Guo L, Wang Q, Liu X, Zeng Y, Wen Q, Zhang S, Kwok HF, Lin Y, Liu J (2017) DAPK1 as an independent prognostic marker in liver cancer. PeerJ 5:e3568. https://doi.org/10.7717/peerj.3568
doi: 10.7717/peerj.3568
pubmed: 28740751
pmcid: 5520959
Liu T, Li Y, Gu H, Zhu G, Li J, Cao L, Li F (2013) p21-Activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2). J Biol Chem 288(5):3359–3369. https://doi.org/10.1074/jbc.M112.384289
doi: 10.1074/jbc.M112.384289
pubmed: 23132866
Martoriati A, Doumont G, Alcalay M, Bellefroid E, Pelicci PG, Marine JC (2005) dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. Oncogene 24(8):1461–1466. https://doi.org/10.1038/sj.onc.1208256
doi: 10.1038/sj.onc.1208256
pubmed: 15608685
Meek DW, Knippschild U (2003) Posttranslational modification of MDM2. Mol Cancer Res 1(14):1017–1026
pubmed: 14707285
Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, Masuyama N, Gotoh Y (2002) Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 277(24):21843–21850. https://doi.org/10.1074/jbc.M109745200
doi: 10.1074/jbc.M109745200
pubmed: 11923280
Pei L, Shang Y, Jin H, Wang S, Wei N, Yan H, Wu Y, Yao C, Wang X, Zhu LQ, Lu Y (2014) DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death. J Neurosci 34(19):6546–6556. https://doi.org/10.1523/JNEUROSCI.5119-13.2014
doi: 10.1523/JNEUROSCI.5119-13.2014
pubmed: 24806680
pmcid: 6608141
Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A (2001) DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol 3(1):1–7. https://doi.org/10.1038/35050500
doi: 10.1038/35050500
pubmed: 11146619
Shafei A, El-Bakly W, Sobhy A, Wagdy O, Reda A, Aboelenin O, Marzouk A, El Habak K, Mostafa R, Ali MA, Ellithy M (2017) A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer. Biomed Pharmacother 95:1209–1218. https://doi.org/10.1016/j.biopha.2017.09.059
doi: 10.1016/j.biopha.2017.09.059
pubmed: 28931213
Shiloh R, Bialik S, Kimchi A (2014) The DAPK family: a structure-function analysis. Apoptosis 19(2):286–297. https://doi.org/10.1007/s10495-013-0924-5
doi: 10.1007/s10495-013-0924-5
pubmed: 24220854
Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96. https://doi.org/10.1038/nrc3430
doi: 10.1038/nrc3430
pubmed: 23303139
pmcid: 4161369
Wang S, Shi X, Li H, Pang P, Pei L, Shen H, Lu Y (2017a) DAPK1 signaling pathways in stroke: from mechanisms to therapies. Mol Neurobiol 54(6):4716–4722. https://doi.org/10.1007/s12035-016-0008-y
doi: 10.1007/s12035-016-0008-y
pubmed: 27447806
Wang S, Zhao Y, Aguilar A, Bernard D, Yang CY (2017b) Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a026245
doi: 10.1101/cshperspect.a026245
pubmed: 28270530
pmcid: 5411684
Wang Q, Ye Y, Lin R, Weng S, Cai F, Zou M, Niu H, Ge L, Lin Y (2020) Analysis of the expression, function, prognosis and co-expression genes of DDX20 in gastric cancer. Comput Struct Biotechnol J 18:2453–2462. https://doi.org/10.1016/j.csbj.2020.09.002
doi: 10.1016/j.csbj.2020.09.002
pubmed: 33005307
pmcid: 7509587
Wang L, Shui X, Mei Y, Xia Y, Lan G, Hu L, Zhang M, Gan CL, Li R, Tian Y, Wang Q, Gu X, Chen D, Zhang T, Lee TH (2022) miR-143–3p inhibits aberrant tau phosphorylation and amyloidogenic processing of APP by directly targeting DAPK1 in Alzheimer’s disease. Int J Mol Sci 23(14):10. https://doi.org/10.3390/ijms23147992
doi: 10.3390/ijms23147992
Wang L, Shui X, Zhang M, Mei Y, Xia Y, Lan G, Hu L, Gan CL, Tian Y, Li R, Gu X, Zhang T, Chen D, Lee TH (2022b) MiR-191-5p attenuates tau phosphorylation, abeta generation, and neuronal cell death by regulating death-associated protein kinase 1. ACS Chem Neurosci 13(24):3554–3566. https://doi.org/10.1021/acschemneuro.2c00423
doi: 10.1021/acschemneuro.2c00423
pubmed: 36454178
Wang Q, Weng S, Sun Y, Lin Y, Zhong W, Kwok HF, Lin Y (2022) High DAPK1 expression promotes tumor metastasis of gastric cancer. Biology (Basel). https://doi.org/10.3390/biology11101488
doi: 10.3390/biology11101488
pubmed: 36671835
pmcid: 10468097
Wood NT, Meek DW, Mackintosh C (2009) 14–3-3 Binding to Pim-phosphorylated Ser166 and Ser186 of human Mdm2–Potential interplay with the PKB/Akt pathway and p14(ARF). FEBS Lett 583(4):615–620. https://doi.org/10.1016/j.febslet.2009.01.003
doi: 10.1016/j.febslet.2009.01.003
pubmed: 19166854
Wu D, Prives C (2018) Relevance of the p53-MDM2 axis to aging. Cell Death Differ 25(1):169–179. https://doi.org/10.1038/cdd.2017.187
doi: 10.1038/cdd.2017.187
pubmed: 29192902
Xie JY, Chen PC, Zhang JL, Gao ZS, Neves H, Zhang SD, Wen Q, Chen WD, Kwok HF, Lin Y (2017) The prognostic significance of DAPK1 in bladder cancer. PLoS ONE 12(4):e0175290. https://doi.org/10.1371/journal.pone.0175290
doi: 10.1371/journal.pone.0175290
pubmed: 28388658
pmcid: 5384764
You MH, Kim BM, Chen CH, Begley MJ, Cantley LC, Lee TH (2017) Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death. Cell Death Differ 24(2):238–250. https://doi.org/10.1038/cdd.2016.114
doi: 10.1038/cdd.2016.114
pubmed: 28141794
Yu Q, Li Y, Mu K, Li Z, Meng Q, Wu X, Wang Y, Li L (2014) Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations. Diagn Pathol 9:71. https://doi.org/10.1186/1746-1596-9-71
doi: 10.1186/1746-1596-9-71
pubmed: 24667108
pmcid: 3986947
Zhang T, Xia Y, Hu L, Chen D, Gan CL, Wang L, Mei Y, Lan G, Shui X, Tian Y, Li R, Zhang M, Lee TH (2022) Death-associated protein kinase 1 mediates Abeta42 aggregation-induced neuronal apoptosis and tau dysregulation in Alzheimer’s disease. Int J Biol Sci 18(2):693–706. https://doi.org/10.7150/ijbs.66760
doi: 10.7150/ijbs.66760
pubmed: 35002518
pmcid: 8741852
Zhao J, Zhao D, Poage GM, Mazumdar A, Zhang Y, Hill JL, Hartman ZC, Savage MI, Mills GB, Brown PH (2015) Death-associated protein kinase 1 promotes growth of p53-mutant cancers. J Clin Invest 125(7):2707–2720. https://doi.org/10.1172/JCI70805
doi: 10.1172/JCI70805
pubmed: 26075823
pmcid: 4563671
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3(11):973–982. https://doi.org/10.1038/ncb1101-973
doi: 10.1038/ncb1101-973
pubmed: 11715018