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Small-molecule exhibits anti-tumor activity by targeting the RNA m6A reader IGF2BP3 in ovarian cancer
Chang Shu1,2, Mao-Hong Gu3, Cheng Zeng4
1General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University Nanjing, Jiangsu, China.
Abstract:
Based on its absence in normal tissues and its role in tumorigenesis and tumor progression, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of N6-methyladenosine (M6A) on RNA, represents a putative valuable and specific target for some cancer therapy. In this study, we performed bioinformatic analysis and immunohistochemistry (IHC) to find that IGF2BP3 was highly expressed in tumor epithelial cells and fibroblasts of ovarian cancer (OC), and was associated with poor prognosis, metastasis, and chemosensitivity in OC patients. In particular, we discovered that knockdown IGF2BP3 expression inhibited the malignant phenotype of OC cell lines by decreasing the protein levels of c-MYC, VEGF, CDK2, CDK6, and STAT1. To explore the feasibility of IGF2BP3 as a therapeutic target for OC, a small molecular AE-848 was designed and screened by molecular operating environment (MOE), which not only could duplicate the above results of knockdown assay but also reduced the expression of c-MYC in M2 macrophages and tumor-associated macrophages and promoted the cytokine IFN-γ and TNF-α secretion. The pharmacodynamic models of two kinds of OC bearing animals were suggested that systemic therapy with AE-848 significantly inhibited tumor growth by reducing the expression of tumor-associated antigen (c-MYC/VEGF/Ki67/CDK2) and improving the anti-tumor effect of macrophages. These results suggest that AE-848 can inhibit the growth and progression of OC cells by disrupting the stability of the targeted mRNAs of IGF2BP3 and may be a targeted drug for OC treatment.
Insights
Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a promising target for ovarian cancer (OC) therapy. A novel small molecule, AE-848, effectively inhibits OC growth by targeting IGF2BP3 and enhancing anti-tumor immunity.
Area of Science:
- Oncology
- Molecular Biology
- RNA Biology
Background:
- Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is implicated in tumorigenesis and tumor progression.
- IGF2BP3 is an N6-methyladenosine (M 6 A) RNA binder, making it a potential therapeutic target.
- Its absence in normal tissues and role in cancer suggest specificity for targeted therapy.
Purpose of the Study:
- To investigate IGF2BP3 as a therapeutic target in ovarian cancer (OC).
- To evaluate the efficacy of a novel small molecule, AE-848, in inhibiting OC growth.
- To elucidate the mechanisms by which IGF2BP3 and AE-848 affect OC progression and anti-tumor immunity.
Main Methods:
- Bioinformatic analysis and immunohistochemistry (IHC) to assess IGF2BP3 expression in OC.
- In vitro studies involving knockdown of IGF2BP3 in OC cell lines.
- In silico screening and in vivo pharmacodynamic studies using AE-848 in OC animal models.
Main Results:
- IGF2BP3 was highly expressed in OC, correlating with poor prognosis, metastasis, and chemosensitivity.
- Knockdown of IGF2BP3 inhibited OC cell malignancy by reducing c-MYC, VEGF, CDK2, CDK6, and STAT1.
- AE-848 mimicked knockdown effects, reduced M2 macrophage c-MYC, and promoted IFN-γ and TNF-α secretion.
- AE-848 significantly inhibited tumor growth in vivo by downregulating tumor antigens and enhancing macrophage anti-tumor activity.
Conclusions:
- IGF2BP3 is a validated therapeutic target for ovarian cancer.
- AE-848 demonstrates potential as a targeted drug for OC treatment by disrupting IGF2BP3 mRNA stability.
- AE-848 exhibits anti-tumor effects through direct inhibition of cancer cell growth and modulation of the tumor microenvironment.
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