• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

分子伴侣在具有突变及MDM2上调的癌细胞获得化学抗性中的作用

Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated and MDM2 up-regulation.

作者信息

Tracz-Gaszewska Zuzanna, Klimczak Marta, Biecek Przemyslaw, Herok Marcin, Kosinski Marcin, Olszewski Maciej B, Czerwińska Patrycja, Wiech Milena, Wiznerowicz Maciej, Zylicz Alicja, Zylicz Maciej, Wawrzynow Bartosz

机构信息

International Institute of Molecular and Cell Biology, Warsaw, Poland.

Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland.

出版信息

Oncotarget. 2017 Jun 30;8(47):82123-82143. doi: 10.18632/oncotarget.18899. eCollection 2017 Oct 10.

DOI:10.18632/oncotarget.18899
PMID:29137250
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5669876/
Abstract

Utilizing the TCGA PANCAN12 dataset we discovered that cancer patients with mutations in tumor suppressor and overexpression of oncogene exhibited decreased survival post treatment. Interestingly, in the case of breast cancer patients, this phenomenon correlated with high expression level of several molecular chaperones belonging to the HSPA, DNAJB and HSPC families. To verify the hypothesis that such a genetic background may promote chaperone-mediated chemoresistance, we employed breast and lung cancer cell lines that constitutively overexpressed heat shock proteins and have shown that HSPA1A/HSP70 and DNAJB1/HSP40 facilitated the binding of mutated p53 to the TAp73α protein. This chaperone-mediated mutated p53-TAp73α complex induced chemoresistance to DNA damaging reagents, like Cisplatin, Doxorubicin, Etoposide or Camptothecin. Importantly, when the oncogene was overexpressed, heat shock proteins were displaced and a stable multiprotein complex comprising of mutated p53-TAp73α-MDM2 was formed, additionally amplifying cancer cells chemoresistance. Our findings demonstrate that molecular chaperones aid cancer cells in surviving the cytotoxic effect of chemotherapeutics and may have therapeutic implications.

摘要

利用TCGA PANCAN12数据集，我们发现肿瘤抑制基因发生突变且癌基因过表达的癌症患者在治疗后生存率降低。有趣的是，在乳腺癌患者中，这种现象与属于HSPA、DNAJB和HSPC家族的几种分子伴侣的高表达水平相关。为了验证这种遗传背景可能促进伴侣介导的化疗耐药性这一假设，我们使用了组成性过表达热休克蛋白的乳腺癌和肺癌细胞系，并表明HSPA1A/HSP70和DNAJB1/HSP40促进了突变型p53与TAp73α蛋白的结合。这种伴侣介导的突变型p53-TAp73α复合物诱导了对DNA损伤试剂（如顺铂、阿霉素、依托泊苷或喜树碱）的化疗耐药性。重要的是，当癌基因过表达时，热休克蛋白被取代，形成了由突变型p53-TAp73α-MDM2组成的稳定多蛋白复合物，进一步增强了癌细胞的化疗耐药性。我们的研究结果表明，分子伴侣有助于癌细胞在化疗药物的细胞毒性作用下存活，可能具有治疗意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/bbe047903757/oncotarget-08-82123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/47480ed6c422/oncotarget-08-82123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/ffd2412b653f/oncotarget-08-82123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/cd85e6604a89/oncotarget-08-82123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/a26d3f5837c8/oncotarget-08-82123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/db2f3ab32fc7/oncotarget-08-82123-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/bbe047903757/oncotarget-08-82123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/47480ed6c422/oncotarget-08-82123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/ffd2412b653f/oncotarget-08-82123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/cd85e6604a89/oncotarget-08-82123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/a26d3f5837c8/oncotarget-08-82123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/db2f3ab32fc7/oncotarget-08-82123-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8675/5669876/bbe047903757/oncotarget-08-82123-g006.jpg

相似文献

1
Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated and MDM2 up-regulation.分子伴侣在具有突变及MDM2上调的癌细胞获得化学抗性中的作用
Oncotarget. 2017 Jun 30;8(47):82123-82143. doi: 10.18632/oncotarget.18899. eCollection 2017 Oct 10.
2
TAp73 alpha increases p53 tumor suppressor activity in thyroid cancer cells via the inhibition of Mdm2-mediated degradation.TAp73α通过抑制Mdm2介导的降解增加甲状腺癌细胞中p53肿瘤抑制活性。
Mol Cancer Res. 2008 Jan;6(1):64-77. doi: 10.1158/1541-7786.MCR-07-0005.
3
Chaperoning the guardian of the genome. The two-faced role of molecular chaperones in p53 tumor suppressor action.分子伴侣监管基因组守护者：p53 肿瘤抑制因子作用的双重角色
Biochim Biophys Acta Rev Cancer. 2018 Apr;1869(2):161-174. doi: 10.1016/j.bbcan.2017.12.004. Epub 2018 Jan 31.
4
Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1.小鼠双微体拮抗剂Nutlin-3a通过激活E2F1增强化疗诱导的p53突变癌细胞凋亡。
Oncogene. 2007 May 24;26(24):3473-81. doi: 10.1038/sj.onc.1210136. Epub 2006 Dec 4.
5
DNAJB1 stabilizes MDM2 and contributes to cancer cell proliferation in a p53-dependent manner.DNAJB1可稳定MDM2，并以p53依赖的方式促进癌细胞增殖。
Biochim Biophys Acta. 2014 Jan;1839(1):62-9. doi: 10.1016/j.bbagrm.2013.12.003. Epub 2013 Dec 19.
6
Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance.HER2和MDM2富集的乳腺癌亚型的化疗诱导同源重组DNA修复和化疗耐药性。
Cancers (Basel). 2021 Sep 7;13(18):4501. doi: 10.3390/cancers13184501.
7
Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms.反义抗MDM2寡核苷酸作为治疗人类乳腺癌的一种新方法：体外和体内活性及作用机制
Clin Cancer Res. 2001 Nov;7(11):3613-24.
8
Induction of p53 expression and apoptosis by a recombinant dual-target MDM2/MDMX inhibitory protein in wild-type p53 breast cancer cells.野生型 p53 乳腺癌细胞中重组双靶点 MDM2/MDMX 抑制蛋白诱导的 p53 表达和细胞凋亡。
Int J Oncol. 2013 Dec;43(6):1935-42. doi: 10.3892/ijo.2013.2138. Epub 2013 Oct 14.
9
Comparative Expression Analysis of Tumor Suppressor and Oncogene in Colorectal Adenocarcinoma.结直肠癌中肿瘤抑制基因与癌基因的比较表达分析
Cancer Diagn Progn. 2024 Mar 3;4(2):129-134. doi: 10.21873/cdp.10298. eCollection 2024 Mar-Apr.
10
Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells.MDM2 抑制剂 nutlin-3 在胃癌细胞中的强大体外和体内抗肿瘤作用。
Cancer Sci. 2011 Mar;102(3):605-13. doi: 10.1111/j.1349-7006.2010.01821.x. Epub 2011 Jan 12.

引用本文的文献

1
Inhibition of CCT5-mediated asparagine biosynthesis and anti-PD-L1 produce synergistic antitumor effects in colorectal cancer.抑制CCT5介导的天冬酰胺生物合成与抗PD-L1在结直肠癌中产生协同抗肿瘤作用。
Acta Pharm Sin B. 2025 May;15(5):2480-2497. doi: 10.1016/j.apsb.2025.03.026. Epub 2025 Mar 14.
2
TP53 mutations and MDM2 polymorphisms in breast and ovarian cancers: amelioration by drugs and natural compounds.乳腺癌和卵巢癌中的TP53突变与MDM2多态性：药物和天然化合物的改善作用
Clin Transl Oncol. 2025 Jan 11. doi: 10.1007/s12094-024-03841-6.
3
Multi-Faceted Roles of DNAJB Protein in Cancer Metastasis and Clinical Implications.

本文引用的文献

1
The Cellular Origin and Evolution of Breast Cancer.乳腺癌的细胞起源与进化
Cold Spring Harb Perspect Med. 2017 Mar 1;7(3):a027128. doi: 10.1101/cshperspect.a027128.
2
The epichaperome is an integrated chaperome network that facilitates tumour survival.表位伴侣蛋白组是一个促进肿瘤存活的整合伴侣蛋白组网络。
Nature. 2016 Oct 20;538(7625):397-401. doi: 10.1038/nature19807. Epub 2016 Oct 5.
3
Emerging roles and underlying molecular mechanisms of DNAJB6 in cancer.DNAJB6在癌症中的新兴作用及潜在分子机制
DNAJB 蛋白在癌症转移中的多方面作用及其临床意义。
Int J Mol Sci. 2022 Nov 29;23(23):14970. doi: 10.3390/ijms232314970.
4
SOX30 Overexpression Reflects Tumor Invasive Degree, Lymph Node Metastasis and Predicts Better Survival in Colorectal Cancer Patients: A Long-Term Follow-Up Cohort Study.SOX30过表达反映结直肠癌患者的肿瘤侵袭程度、淋巴结转移情况并预测更好的生存：一项长期随访队列研究
Front Surg. 2022 Jun 28;9:898952. doi: 10.3389/fsurg.2022.898952. eCollection 2022.
5
Temozolomide increases heat shock proteins in extracellular vesicles released from glioblastoma cells.替莫唑胺增加了从胶质母细胞瘤细胞释放的细胞外囊泡中的热休克蛋白。
Mol Biol Rep. 2022 Sep;49(9):8701-8713. doi: 10.1007/s11033-022-07714-5. Epub 2022 Jun 25.
6
DNAJB8 in small extracellular vesicles promotes Oxaliplatin resistance through TP53/MDR1 pathway in colon cancer.小细胞外囊泡中的 DNAJB8 通过 TP53/MDR1 通路促进结肠癌对奥沙利铂的耐药性。
Cell Death Dis. 2022 Feb 14;13(2):151. doi: 10.1038/s41419-022-04599-x.
7
miR-1205/DNAJB1 reverses docetaxel chemoresistance in human triple negative breast carcinoma cells via regulation of mutp53/TAp63 signaling.miR-1205/DNAJB1 通过调节 mutp53/TAp63 信号逆转人三阴性乳腺癌细胞对多西他赛的化疗耐药性。
Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(1):37-46. doi: 10.3724/abbs.2021006.
8
Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53 Uterine Leiomyosarcoma.在p53子宫平滑肌肉瘤中联合使用MDM2和WIP1抑制剂将生长抑制转变为凋亡
Cancers (Basel). 2021 Dec 21;14(1):14. doi: 10.3390/cancers14010014.
9
Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members.热休克蛋白 40/J 结构域蛋白家族成员对 p53 和癌症信号的调控。
Int J Mol Sci. 2021 Dec 16;22(24):13527. doi: 10.3390/ijms222413527.
10
The p53 family member p73 in the regulation of cell stress response.p53 家族成员 p73 在细胞应激反应调控中的作用。
Biol Direct. 2021 Nov 8;16(1):23. doi: 10.1186/s13062-021-00307-5.
Oncotarget. 2016 Aug 16;7(33):53984-53996. doi: 10.18632/oncotarget.9803.
4
Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport.内质网驻留热休克蛋白90（HSP90）异构体葡萄糖调节蛋白94（GRP94）通过影响细胞内运输来调节细胞极性和癌细胞迁移。
J Biol Chem. 2016 Apr 15;291(16):8309-23. doi: 10.1074/jbc.M115.688374. Epub 2016 Feb 12.
5
Metazoan Hsp70-based protein disaggregases: emergence and mechanisms.基于后生动物热休克蛋白70的蛋白质解聚酶：出现与机制
Front Mol Biosci. 2015 Oct 9;2:57. doi: 10.3389/fmolb.2015.00057. eCollection 2015.
6
The Role of MicroRNAs in the Chemoresistance of Breast Cancer.微小RNA在乳腺癌化疗耐药中的作用
Drug Dev Res. 2015 Nov;76(7):368-74. doi: 10.1002/ddr.21275. Epub 2015 Aug 27.
7
HSPA12B: a novel facilitator of lung tumor growth.热休克蛋白家族A（Hsp70）成员12B：一种促进肺肿瘤生长的新因子。
Oncotarget. 2015 Apr 30;6(12):9924-36. doi: 10.18632/oncotarget.3533.
8
The role of heat shock proteins in cancer.热休克蛋白在癌症中的作用。
Cancer Lett. 2015 May 1;360(2):114-8. doi: 10.1016/j.canlet.2015.02.026. Epub 2015 Feb 23.
9
HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models.HSP90促进人类乳腺癌模型中激素疗法耐药性的演变。
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18297-302. doi: 10.1073/pnas.1421323111. Epub 2014 Dec 8.
10
Functional interplay between MDM2, p63/p73 and mutant p53.MDM2、p63/p73与突变型p53之间的功能相互作用。
Oncogene. 2015 Aug 13;34(33):4300-10. doi: 10.1038/onc.2014.359. Epub 2014 Nov 24.