Fanconi anemia complementation group-F (FANCF) is a key factor to maintain the function of FA/BRCA, a DNA-damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. In this study, we examined the effects and mechanisms of FANCF-RNAi on the sensitivity of breast cancer cells to mitoxantrone (MX). FANCF silencing by FANCF-shRNA blocked functions of FA/BRCA pathway through inhibition of FANCD2 mono-ubiquitination in breast cancer cell lines MCF-7 and T-47D. In addition, FANCF shRNA inhibited cell proliferation, induced apoptosis, and chromosome fragmentation in both breast cancer cells. We also found that FANCF silencing potentiated the sensitivity to MX in breast cancer cells, accompanying with an increase in intracellular MX accumulation and a decrease in BCRP expression. Furthermore, we found that the blockade of FA/BRCA pathway by FANCF-RNAi activated p38 and JNK MAPK signal pathways in response to MX treatment. BCRP expression was restored by p38 inhibitor SB203580, but not by JNK inhibitor SP600125. FANCF silencing increased JNK and p38 mediated activation of p53 in MX-treated breast cancer cells, activated the mitochondrial apoptosis pathway. Our findings indicate that FANCF shRNA potentiates the sensitivity of breast cancer cells to MX, suggesting that FANCF may be a potential target for therapeutic strategies for the treatment of breast tumors.
The flower of
Trollius chinensis Bunge
was widely used for the treatment of inflammation-related diseases in traditional Chinese medicine (TCM). In order to clarify the anti-inflammatory mechanism of this Chinese herbs, a comprehensive network pharmacology strategy that consists of three sequential modules (pharmacophore matching, enrichment analysis and molecular docking.) was carried out. As a result, Apoptosis signal-regulating kinase 1 (ASK1), Janus kinase 1 (JAK1), c-Jun N-terminal kinases (JNKs), transforming protein p21 (HRas) and mitogen-activated protein kinase 14 (p38α) that related to the anti-inflammatory effect were filtered out. In further molecular dynamics (MD) simulation, the conformation of CID21578038 and CID20055288 were found stable in the protein ASK1 and JNKs respectively. The current investigation revealed that two effective compounds in the flower of
Trollius chinensis Bunge
played a crucial role in the process of inflammation by targeting ASK1 and JNKs, the comprehensive strategy can serve as a universal method to guide in illuminating the mechanism of the prescription of traditional Chinese medicine by identifying the pathways or targets.
Cyclin-dependent kinase 2 (CDK2) is the family of Ser/Thr protein kinases that has emerged as a highly selective with low toxic cancer therapy target. A multistage virtual screening method combined by SVM, protein-ligand interaction fingerprints (PLIF) pharmacophore and docking was utilised for screening the CDK2 inhibitors. The evaluation of the validation set indicated that this method can be used to screen large chemical databases because it has a high hit-rate and enrichment factor (80.1% and 332.83 respectively). Six compounds were screened out from NCI, Enamine and Pubchem database. After molecular dynamics and binding free energy calculation, two compounds had great potential as novel CDK2 inhibitors and they also showed selective inhibition against CDK2 in the kinase activity assay.
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