MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Jianling Bi; Sudartip Areecheewakul; Yujun Li; Shujie Yang; Yuping Zhang; Kareem Ebeid; Long Li; Kristina W Thiel; Jun Zhang; Donghai Dai; Aliasger K Salem; Kimberly K Leslie; Xiangbing Meng

doi:10.1016/j.ygyno.2019.08.014

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MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

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Peer reviewed

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Jianling Bi, Sudartip Areecheewakul, Yujun Li, Shujie Yang, Yuping Zhang, Kareem Ebeid, Long Li, Kristina W Thiel, Jun Zhang, Donghai Dai, …

Gynecologic oncology, Vol.155(2), pp.349-358

11/2019

DOI: 10.1016/j.ygyno.2019.08.014

PMCID: PMC6825893

PMID: 31477281

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Abstract

Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined. The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerin-loaded nanoparticles, cisplatin and a combination of the two. MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin. MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.

Animals

Antineoplastic Agents - pharmacology

Cisplatin - pharmacology

Cystadenocarcinoma, Serous - drug therapy

Down-Regulation

Drug Resistance, Neoplasm - drug effects

Fanconi Anemia Complementation Group D2 Protein - antagonists & inhibitors

Fanconi Anemia Complementation Group Proteins - antagonists & inhibitors

Female

Male

Membrane Proteins - drug effects

Mice, Knockout

Nanoparticles

RNA-Binding Proteins

Triterpenes - pharmacology

Uterine Neoplasms - drug therapy

Details

Title: Subtitle: MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy
Creators: Jianling Bi - University of Iowa
Sudartip Areecheewakul - University of Iowa
Yujun Li - University of Iowa
Shujie Yang - University of Iowa
Yuping Zhang - University of Iowa
Kareem Ebeid - University of Iowa
Long Li - University of Iowa
Kristina W Thiel - University of Iowa
Jun Zhang - University of Kansas
Donghai Dai - University of Iowa
Aliasger K Salem - University of Iowa
Kimberly K Leslie - University of Iowa
Xiangbing Meng - University of Iowa
Resource Type: Journal article
Publication Details: Gynecologic oncology, Vol.155(2), pp.349-358
DOI: 10.1016/j.ygyno.2019.08.014
PMID: 31477281
PMCID: PMC6825893
NLM abbreviation: Gynecol Oncol
ISSN: 0090-8258
eISSN: 1095-6859
Grant note: R37 CA238274 / NCI NIH HHS P30 ES005605 / NIEHS NIH HHS R01 CA184101 / NCI NIH HHS R01 CA099908 / NCI NIH HHS P30 CA086862 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
Language: English
Date published: 11/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Craniofacial Anomalies Research Center; Obstetrics and Gynecology; Dental Research; Chemical and Biochemical Engineering; Internal Medicine
Record Identifier: 9984186539402771

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