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Glioblastoma multiforme (GBM) is defined by rapid progression, high invasiveness, and a poor prognosis, with a median survival of only ≅13 months despite current treatments. Its marked genetic heterogeneity, high mutational burden, and cancer stem cell population make GBM exceptionally difficult to treat, highlighting the urgent need for more effective, multitargeted therapies. Non-coding RNAs, particularly tumor suppressor microRNAs (miRNAs), have gained attention for suppressing key oncogenic processes that drive tumorigenesis, metastasis, and drug resistance, positioning them as promising tools for targeting multiple oncogenic pathways. We recently found that FOXM1/AXL-eEF2K collaboratively drive GBM cell proliferation, survival, and invasion through the formation of a signaling hub complex. In this study, we employed miRNA prediction algorithms to identify a specific miRNA, in vitro functional assays and in vivo GBM flank model to target GBM tumorigenesis by distrupting the FOXM1/AXL-eEF2K signaling hub. Our results indicated that FOXM1, AXL, and eEF2K are overexpressed in GBM patient tumors. To target the FOXM1/AXL-eEF2K signaling hub, we identified miR-449b-5p, miR-329-3p, and miR-518c as potential co-inhibitors of FOXM1/AXL-eEF2K and suppressors of cell proliferation, migration-invasion, and spheroid formation. Furthermore, the combination of miR-449b-5p, miR-329-3p, and miR-518c treatments with temozolomide led to synergistic enhancements in cell proliferation suppression and the induction of apoptosis and ferroptosis. More importantly, in vivo miR-329-3p treatment led to remarkable suppression of GBM tumor xenografts. These findings indicate that miR-329-3p-based tumor suppressor therapy may offer a multitargeted approach for GBM treatment.

Cysteine-rich angiogenic inducer 61 (CYR61) promotes prostate cancer (PCa) cell growth, but its role in disease progression remains unclear. Given its insulin-like growth factor (IGF)-binding domain and the known involvement of insulin-like growth factor-1 (IGF1) in PCa, we investigated the molecular interplay between CYR61 and IGF1. CYR61 was silenced using small interfering RNA (siRNA) in prostate carcinoma 3 (PC3), lymph node carcinoma of the prostate (LNCaP), and androgen receptor (AR)-positive 22Rv1 cells, followed by assessments of their proliferation, viability, colony formation, migration, and signaling pathway activation. CYR61 knockdown significantly reduced cell growth, viability, prostasphere formation, and migration across all three cell lines. Mechanistically, CYR61 silencing inhibited PI3K/AKT signaling but had no effect on MAPK activation. In addition, treatment with recombinant IGF1 induced CYR61 expression in a time-dependent manner, and the inhibition of PI3K/AKT signaling suppressed both CYR61 expression and cell proliferation. These findings suggest that IGF1 promotes PCa progression through CYR61 and that CYR61 may serve as a potential therapeutic target for limiting tumor growth and metastasis.

ABSTRACTCD36 is a transmembrane glycoprotein that facilitates the uptake of fatty acids and oxidized low‐density lipoproteins. CD36 is overexpressed in various types of cancer and CD36+ cancer cells display enhanced malignancy, including resistance to therapy and elevated stemness and metastatic ability. Thus, CD36 is a therapeutic target in cancer. This study aimed to discover new CD36 antagonists through virtual screening. We identified a druggable pocket in CD36 that is functionally relevant and serves as the binding site for reported antagonists. Consensus molecular docking of a chemical library containing over 25,000 drug‐like compounds identified 15 computational hits with structural diversity. Experimental evaluation of seven compounds revealed that compounds 8, 13, and 14 are novel inhibitors of CD36‐mediated palmitate and/or oxLDL uptake in cellular models. Compound 14 reduced the clonogenicity of HepG2 cells without impacting cell viability, showing that it modulates CD36‐triggered phenotypes associated with disease progression. Analysis of molecular interactions of compounds 8, 13, or 14 with CD36 by molecular dynamics simulations showed that the identified antagonists had stable binding and favorable binding energy, leading to distinct conformational states of the protein. These results support the use of the antagonists identified here as lead compounds for developing CD36‐targeted therapies. Virtual screening identified drug‐like molecules as potential CD36 antagonists; some of them inhibited CD36 function in relevant cellular models. These antagonists could drive the development of CD36‐targeted therapies.