No abstract

BackgroundRelease of exosomes have been shown to play critical roles in drug resistance by delivering cargo. Targeting the transfer of exosomes from resistant cells to sensitive cells may be an approach to overcome some cases of drug resistance.MethodIn this study, we investigated the potential role of exosomes in the process of psoralen reverse multidrug resistance of MCF-7/ADR cells. Exosomes were isolated by differential centrifugation of culture media from MCF-7/ADR cells (ADR/exo) and MCF-7 parental cells (S/exo). Exosomes were characterized by morphology, exosomal markers and size distribution. The ability of ADR/exo to transfer multidrug resistance was assessed by MTT and real-time quantitative PCR. The different formation and secretion of exosomes were detected by immunofluorescence and transmission electron microscopy. Then we performed comparative transcriptomic analysis using RNA-Seq technology and real-time quantitative PCR to better understand the gene expression regulation in exosmes formation and release after psoralen treatment.ResultsOur data showed that exosomes derived from MCF-7/ADR cells were able to promote active sequestration of drugs and could induce a drug resistance phenotype by transferring drug-resistance-related gene MDR-1 and P-glycoprotein protein. Psoralen could reduce the formation and secretion of exosomes to overcome drug resistance. There were 21 differentially expressed genes. Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to PPAR and P53 signaling pathways which were related to exosomes formation, secretion and cargo sorting.ConclusionsPsoralen can affect the exosomes and induce the reduction of resistance transmission via exosomes might through PPAR and P53 signaling pathways, which might provide a novel strategy for breast cancer resistance to chemotherapy in the future.

Psoralen is a major active component of Psoralea corylifolia. In the present study, we analyzed psoraleninduced changes in human breast cancer MCF-7/ADR cells and investigated the underlying mechanisms of the anticancer effect on MCF-7/ADR cells. We measured cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the cytotoxicity and multidrug resistance (MDR) reversal activity of psoralen. The cell cycle distribution and apoptosis, accumulation and efflux of rhodamine123 (Rh123), and P-glycoprotein (P-gp) expression levels of MCF-7/ADR cells treated with psoralen were all detected by flow cytometry (FCM). We assessed P-gp ATPase activity by monitoring ATP consumption. We evaluated the activity of nuclear factor-kappaB (NF-κB) and the expression of E-cadherin, vimentin and α-smooth muscle actin (SMA) involved in regulating epithelial-mesenchymal transition (EMT). The results showed that psoralen inhibited the proliferation of MCF-7/ADR cells as shown by G0/G1 phase arrest rather than encouraging apoptosis. It was also observed that psoralen reversed MDR through inhibiting ATPase activity rather than reducing P-gp expression. Our results further showed that psoralen inhibited the migration abilities of MCF-7/ADR cells by repressing EMT possibly through inhibiting the activation of NF-κB. Our findings provided a systematic and detailed description of the anti-cancer effect of psoralen on MCF-7/ ADR cells for the exploration of natural compounds as novel anticancer agents.Key words psoralen; multidrug resistance (MDR); P-glycoprotein (P-gp) ATPase; cell cycle arrest; epithelial-mesenchymal transition (EMT)The breast cancer incidence in Asia is rising as the leading cause of cancer death among women in the world. It is a systemic disease, with the primary tumor representing the localized form of the disease. At present, the main treatment for breast cancer include chemotherapy, surgery, radiotherapy, hormonal therapy and targeted antibodies. The overall treatment effect is reassuring, but still facing many thorny issues, lacking of specificity and poor avoidance of recurrence. The chemotherapy resistance, the metastasis and recurrence, these are all the reasons for breast cancer treatment failure. Plantderived natural products play a very important role in the area of cancer therapy research as a source of numerous currently used anticancer agents 1) including vincristine, vinblastine, paclitaxel, camptothecin derivatives, epipodophyllotoxin, and many others.2) Therefore, there is a great need for continuous search for new antineoplastic agents from plant sources.In the 1970s, Psoralea corylifolia is widely distributed in Southeastern Asian countries had inspired scientific interest with clinical applications, 3) and then it is officially listed in the Pharmacopoeia of the traditional Chinese medicine (TCM) (Edit 2010 Vol. II). As is known to all, two of the main ingredients of furanocoumarins are psoralen and isopsoralen which play a role in cell proliferation and diff...

High lncRNA ATB expression was significantly associated with worse prognosis in cancer. LncRNA ATB expression could be used as a prognostic biomarker for human cancer.