MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases
Jianling Bi1, Sudartip Areecheewakul2, Yujun Li1
1Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Metadherin (MTDH) drives platinum resistance by regulating FANCD2 and FANCI. Pristimerin, a novel compound, restores sensitivity to platinum chemotherapy by inhibiting MTDH and the Fanconi anemia pathway.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Platinum compounds are crucial cancer therapeutics.
- Therapeutic resistance to platinum agents is a significant clinical challenge.
- Metadherin (MTDH) is implicated in chemoresistance, but its mechanisms are unclear.
Purpose of the Study:
- To elucidate the role of MTDH in platinum resistance.
- To investigate the potential of pristimerin in overcoming MTDH-driven platinum resistance.
- To evaluate the efficacy of pristimerin in combination with platinum chemotherapy.
Main Methods:
- RNA-binding protein immunoprecipitation to assess MTDH interactions.
- Nanoparticle formulation of pristimerin for drug delivery.
- In vivo studies using patient-derived xenograft models in immunocompromised mice.
Main Results:
- MTDH regulates FANCD2 and FANCI expression, key in platinum-induced DNA damage repair.
- Pristimerin reduces MTDH, FANCD2, and FANCI levels, restoring platinum sensitivity.
- Combination therapy with pristimerin nanoparticles and cisplatin significantly inhibited tumor growth in a xenograft model.
Conclusions:
- MTDH mediates post-transcriptional regulation of FANCD2 and FANCI.
- Pristimerin enhances platinum-based chemotherapy efficacy in MTDH-overexpressing tumors by inhibiting the Fanconi anemia pathway.
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