|Table of Contents|

The activity and mechanism of MDM2/MDMX inhibitory protein in mt-p53 breast cancer

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2020 05
Page:
713-719
Research Field:
Publishing date:

Info

Title:
The activity and mechanism of MDM2/MDMX inhibitory protein in mt-p53 breast cancer
Author(s):
Geng Qianqian1Chen Nanzheng2Dong Danfeng3Wu Yinying3Li Enxiao3
1.Department of Nuclear Medicine;2.Thoracic Surgery;3.Medical Oncology of the First Affiliated Hospital of Xi'an Jiaotong University,Shaanxi Xi'an 710061,China.
Keywords:
MDM2MDMXrecombination proteinmt-p53breast cancer
PACS:
R737.9
DOI:
10.3969/j.issn.1672-4992.2020.05.005
Abstract:
Objective:To determine the anti-tumor effect and possible mechanism of MDM2/MDMX dual-target inhibitory protein in p53 mutant breast cancer.Methods:To assess the activity and mechanism of MDM2/MDMX inhibitory protein in mt-p53 breast cancer.Cell viability,cell cycle distribution and apoptosis were detected by MTT assay,flow cytometry (FCM) and Annexin V/FITC-PI staining.MDM2,MDMX,p53,PUMA,bax and p21 proteins were carried out by Western Blot assay.Results:There were significant differences between MDM2/MDMX inhibitory protein and Nutlin-3α in inhibiting cell proliferation of mt-p53 breast cancer cells for 24 h and 48 h (P<0.05).The proportions of G0/G1 phase cells treated with MDM2/MDMX inhibitory protein for 24 h and 48 h were significantly higher than that of Nutlin-3α treatment (P<0.05).The early stage apoptotic cells of MDA-MB-321 treated with MDM2/MDMX inhibitory protein were (15.97±1.48)% for 24 h and (17.80±2.21)% for 48 h[BT-474 cells:(11.09±2.45)% for 24 h and (10.44±2.90)% for 48 h].In mt-p53 breast cancer cells,the expression of MDM2 and MDMX protein was significantly decreased in the inhibitory protein group,and the p53 protein was not significantly changed.The expression of PUMA,p21 and bax protein was all significantly up-regulated.Conclusion:MDM2/MDMX inhibitory protein inhibited cell proliferation,induced cell cycle arrest in G0/G1 phase and apoptosis in mt-p53 breast cancer cells.The inhibitory protein could successfully bind with MDM2 and MDMX,but cannot activate p53 in mt-p53 breast cancer cell.p21,bax and PUMA proteins were up-regulated for realization of antitumor activity by the way of p53-independent in mt-p53 breast cancer.

References:

[1]Khoo KH,Verma CS,Lane DP.Drugging the p53 pathway:Understanding the route to clinical efficacy[J].Nature Review Drug Discovery,2014(13):217-236.
[2]Skalniak L,Surmiak E,Holak TA.A therapeutic patent overview of MDM2/X-targeted therapies (2014-2018)[J].Expert Opinion On Therapeutic Patents,2019(29):151-170.
[3]Chatterjee N,Walker GC.Mechanisms of DNA damage,repair,and mutagenesis[J].Environmental and Molecular Mutagenesis,2017,59(5):235-263.
[4]Cai BH,Chao CF,Huang HC,et al.Roles of p53 family structure and function in non-canonical response element binding and activation[J].International Journal of Molecular Sciences,2019,20(15):e3681.
[5]Yi Y,Zhang W,Yi J,et al.Role of p53 family preoteins in metformin anti-cancer activities[J].Journal of Cancer,2019,10(11):2434-2442.
[6]Blandino G,Valenti F,Sacconi A,et al.Wild-type and mutant p53 proteins in mitochondrial dysfunction:Emerging insights in cancer disease[J].Seminars in Cell and Developmental Biology,2019,5(18):S1084.
[7]Wang W,Qin JJ,Rajaei M,et al.Targeting MDM2 for novel molecular therapy:Beyond oncology[J].Medical Research Review,2019,10(6):e21637.
[8]Lucia H,Borivoj V.HDM2 and HDMX proteins in human cancer[J].Klin Oncology,2018(31):63-71.
[9]Bardot B,Toledo F.Targeting MDM4 splicing in cancers[J].Genes,2017,8(2):e82.
[10]Karni-Schmidt O,Lokshin M,Prives C.The roles of MDM2 and MDMX in cancer[J].Annual Review of Pathology-Mechanisms of Disease,2016(11):617-644.
[11]Gena QQ,Dong DF,Chen NZ,et al.Induction of p53 expression and apoptosis by a recombinant dual-target MDM2/MDMX inhibitory protein in wild-type p53 breast cancer cells[J].Int J Oncol,2013(43):1935-1942.
[12]Noguchi T,Oishi S,Honda K,et al.Affinity-based screening of MDM2/MDMX-p53 interaction inhibitors by chemical array:Identification of novel peptidic inhibitors[J].Bioorganic and Medicinal Chemistry Letters,2013,23(13):3802-3805.
[13]Liu Y,Wang X,Wang G,et al.The past,present ad future of potential small molecular drugs targeting p53-MDM2/MDMX for cancer therapy[J].European Journal of Medicinal Chemistry,2019(15):92-104.
[14]Qin JJ,Lin X,Hunt C,et al.Natural products targeting the p53-MDM2 pathway and mutant p53:Recent advances and implications in cancer medicine[J].Genes and Diseases,2018(5):204-219.
[15]Qiu P,Guan H,Dong P,et al.The p53-,Bax-and p21-dependent inhibition of colon cancer cell growth by 5-hydroxy polymethoxyflavones[J].Molecular Nutrion and Food Research,2011,55(4):613-622.
[16]IGnacio RM,Dong YL,Kabir SM,et al.CXCR2 is a negative regulator of p21 in p53 dependent and independent manner via Akt mediated Mdm2 in overian cancer[J].Oncotarget,2018,9(11):9751-9765.
[17]Giono LE,Resnick-silverman L,Carvajal LA,et al.Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase[J].Oncogene,2017,36(49):6762-6773.
[18]He K,Zheng X,Zhang L,et al.Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax[J].Molecular Cancer Therapeutics,2013,12(11):2559-2568.
[19]Lau CK,Yang ZF,Lam CT,et al.Suppression of hypoxia inducible factor-1alpha (HIF-1alpha) by YC-1 is dependent on murine double minute 2 (Mdm2)[J].Biochemical and Biophysical Research Communications,2006,348(4):1443-1448.
[20]Sun W,Tang L.MDM2 increase drug resistance in cancer cells by inducing EMT independent of p53[J].Current Medicinal Chemistry,2016,23(40):4529-4539.
[21]Huang L,Li A,Liao G,et al.Curcumol trigger apoptosis of p53 mutant triple-nergative human breast cancer MDA-MB-231 cell via activation of p74 and PUMA[J].Oncology Letters,2017,14(1):1080-1088.
[22]Pasello G,Urso L,Mencoboni M,et al.MDM2 and HIF alpha expression levels in different histolodic subtypes of malignant pleural mesothelioma:Correlation with pathological and clinical data[J].Oncotarget,2015,6(39):42053-42066.
[23]Zhang J,Huang K,O'neill KL,et al.Bax/Bak activation in the absence of Bid,Bim,Puma,and p53[J].Cell Death and Disease,2016(7):e2266.

Memo

Memo:
National Natural Science Foundation of China(No.81803015);国家自然科学基金资助项目(编号:81803015)
Last Update: 1900-01-01