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

Abstract

h i g h l i g h t sEndometrial cancer patients with high copy number of MTDH show poor outcome.Inhibition MTDH increases DNA damage induced g-H2Ax foci formation and sensitivity to cisplatin.MTDH binds with mRNAs encoding for FANCD2 and FANCI. Pristimerin-loaded nanoparticles inhibit MTDH, FANCD2 and FANCI to increase sensitivity to cisplatin. a b s t r a c tObjective: 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 pristimerinloaded 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.

Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance

“…However, the RNA interactome was not characterized, and it was documented that the protein levels of two AEG-1-interacting mRNAs, PDCD11 and KDM6A, were increased in AEG-1 knockdown cells, and the consequence of this observation was not studied [ 134 ]. In a follow-up study, the authors showed that, using residues 145-216, AEG-1 bound to mRNAs of FANCD2 and FANCI, two components of the Fanconi anemia complementation group that play an important role in interstrand crosslink damage induced by platinum compounds, increased their protein levels [ 184 ]. A positive correlation among the levels of AEG-1, FANCD2 and FANCI were observed in breast and endometrial cancers.…”

“…A positive correlation among the levels of AEG-1, FANCD2 and FANCI were observed in breast and endometrial cancers. Knocking out AEG-1 increased the cisplatin sensitivity in endometrial cancer cells, but a direct role of FANCD2 and FANCI in mediating this effect was not tested by overexpression/knockdown studies [ 184 ].…”

“…Additionally, the gene expression analysis suggested a potential role of calbindin 1 and galectin-1 in contributing to AEG-1-mediated therapeutic resistance [ 226 ]. AEG-1 positively regulates the expression of FANCD2 and FANCI, which regulates DNA damage by platinum compounds, and knocking out AEG-1 in endometrial cancer cells significantly increased their sensitivity to cisplatin [ 184 ]. Pristimerin, a traditional Chinese medicine, significantly decreased the AEG-1, FANCD2 and FANCI levels in endometrial cancer cells and restored their sensitivity to cisplatin in an in vivo xenograft model [ 184 ].…”

“…AEG-1 positively regulates the expression of FANCD2 and FANCI, which regulates DNA damage by platinum compounds, and knocking out AEG-1 in endometrial cancer cells significantly increased their sensitivity to cisplatin [ 184 ]. Pristimerin, a traditional Chinese medicine, significantly decreased the AEG-1, FANCD2 and FANCI levels in endometrial cancer cells and restored their sensitivity to cisplatin in an in vivo xenograft model [ 184 ]. In multiple cervical cancer cell lines, the overexpression of AEG-1 induced autophagy and activated the ERK/NF-κB pathway, conferring a resistance to cisplatin [ 227 ].…”

The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B

“…Based on previous findings, RBP-, miRNA-, and lncRNA-mediated post-transcriptional regulatory processes also play important roles in regulating the sensitivity to chemotherapeutic agents. 17 , 18 , 19 For the ovarian cancer cells displayed in Figure 8 A, the 50% inhibitory concentration (IC 50 ) of cisplatin was measured. Compared with the IC 50 value of the NC group, the IC 50 values of CELF2-overexpressing CAOV-3 and SK-OV-3 cells were decreased, and the values of CELF2-knockdown A2780 and OVCAR-8 cells increased after treatment with different concentrations of cisplatin, suggesting that the upregulation of CELF2 may be a promising strategy to increase the sensitivity of ovarian cancer cells to cisplatin.…”