Anticancer Activity of Melittin-Containing Bee Venom Fraction Against Glioblastoma Cells In VitroMałek, Strzemski, Kapka-Skrzypczak
et alInt J Mol Sci (2025) 26 (6)
Abstract: Previous observations indicating a lower incidence of various types of cancer in beekeepers suggest that greater exposure to stings reduces the risk of cancer development. However, it is not known which of the active compounds of the bee venom (BV) may be responsible for the observed properties. The aim of this study is to evaluate the anti-glioblastoma effect of the main BV fractions. In addition, the effect of BV fractions on the activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) was assessed. Commercially available BV was divided into three fractions containing one of the main BV components: apamin (fraction #1), phospholipase A2 (fraction #2), or melittin (fraction #3). The viability of glioblastoma lines (LN18 and LN229) compared to a physiological line (human MO3.13) was assessed using the MTT. MMP-2 and MMP-9 activity was assessed using gelatin zymography. Tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) levels in cell culture media were measured with the ELISA method. The fraction containing apamin did not show cytotoxic activity up to a concentration of 100 µg/mL. The fraction containing phospholipase A2 partially reduced the cells' viability at a concentration of 100 µg/mL. The greatest activity was demonstrated by the melittin-containing fraction which completely reduced the viability of glioma cells from a concentration of 2.5 μg/mL and inhibited the activity of the assessed metalloproteinases in a dose-dependent manner. After 72 h of incubation, the highest concentrations of TIMP-1 and TIMP-2 (approximately 150 ng/mL and 100 ng/mL, respectively) were observed in the LN229 line. In all tested lines, fraction #3, crude BV, and melittin reduced the secretion of both inhibitors into the medium in a dose-dependent manner. The melittin-containing fraction possessed anti-glioma properties in vitro, suggesting that melittin may be the main anticancer compound of BV.
XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1Sun, Wang, Liu
et alCell Death Dis (2025) 16 (1), 205
Abstract: X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.© 2025. The Author(s).
TIMP-2 Modulates 5-Fu Resistance in Colorectal Cancer Through Regulating JAK-STAT Signalling PathwayXu, Zhu, Dai
et alJ Cell Mol Med (2025) 29 (6), e70470
Abstract: The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK-STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK-STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK-STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK-STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Association of certain biochemical parameters related to bone cycle with genotype in MPS IIIB patientsGökkurt, Peker Eyüboğlu, Nur Güzel
et alTurk J Med Sci (2025) 55 (1), 328-336
Abstract: The aims of this study are to investigate the genotype-phenotype correlation in Sanfilippo type B (MPS IIIB) patients in terms of bone formation/resorption parameters and to determine the release/inhibition of biomarkers accompanying osteoporosis.Plasma levels of osteoprotegerin (OPG), matrix metalloproteinases (MMP2 and MMP9), tissue inhibitors of metalloproteinase (TIMP1 and TIMP2) and cathepsin K were examined using the ELISA method for a MPS IIIB patient group and a control group. At the same time, mutations in the NAGLU gene causing the disease were identified by whole exome sequencing, and their correlation with biochemical parameters was investigated.The enzyme analysis results showed that MMP2, MMP9, TIMP1, and TIMP2 were significantly high in the study group, while cathepsin K was low. OPG levels were similar between the two groups. The genetic analysis of patients with MPS IIIB was performed by sequencing all exons and exon-intron junction regions of the NAGLU gene using a next-generation sequencing (NGS) system. In this way, variations were detected qualitatively with high read depths. The analyses found that only two patients had a previously pathogenically defined alteration. In addition, the impact assessment analyses detected alterations with a modifying effect on protein structure.The genetic analysis results indicate the need to consider a variation classified as benign in the OMIM database as pathogenic because the variations found in the patients (p.Arg737Gly and p.Trp103Cys) have somehow altered enzyme activity. The mutation p.Trp103Cys, a novel NAGLU gene mutation in the first exon, was detected in one patient; additionally, SIFT and PolyPhen analyses confirmed it as damaging. Further functional analyses of this variation should be conducted to gather more comprehensive information.© TÜBİTAK.
膜杰作
Star Staining
