Abstract Intrinsic drug resistance is the main reason leading to the failure of chemotherapy in lung cancer. Many drug-resistance related proteins such as P-glycoprotein (P-gp), multidrug-resistance protein (MRP), lung resistance-related protein (LRP), glutathione-s-transferase-π (GST-π) and TopoisomeraseIIα (TopoIIα) are thought to be contributed to the chemoresistance. However, only few studies focus on these five mediators together in intrinsic drug resistance in human lung cancer cell lines. Our study aimed at analyzing the relationship between the basal expression of P-gp, MRP, LRP, GST-π and TopoIIα and intrinsic drug resistance in four different histological types of human lung cancer lines of adenocarcinoma, squamous cell carcinoma, small cell carcinoma and large cell carcinoma (SK-MES-1, SPCA-1, NCI-H-460 and NCI-H-446). The expressions of P-gp, MRP, LRP, GST-π and TopoIIα at protein and mRNA level in the four cell lines were initially detected with immunofluorescence, western blot and RT-PCR. Drug resistance to cisplatin, doxorubicine and VP-16 were determined using MTT through the assay of cell viability. Correlation between the expression of the proteins and resistance to the drugs were analyzed as well. There were positive expressions of the proteins of P-gp, MRP, LRP, GST-π and TOPOIIα in all the four types of cell lines no matter assayed by Western blot or RT-PCR, however, the expression levels were different. Among them, GST-π was the most obviously high, its expression at protein level in SK-MES-1 is more than 3-fold higher compared with that in NCI-H-446, and its expression at mRNA level elevated more than 1.4-fold parallelly. The chemosensitivity to cisplatin, doxorubicine and VP-16 for the four cell lines were different. For cisplatin, its IC50 for SK-MES-1 was the highest compared with other three cell lines with about 2–4-fold elevation; for doxorubicin, its IC50 for SK-MES-1 was the highest as well; but for VP-16, its IC50for SK-MES-1 was the lowest (P<0.05). Pearson correlate analysis indicated that there was a positive correlation between the expression of GST-π and resistance to cisplatin and the expression of TOPOIIα toVP-16 (p<0.05), whereas there was a negative correlation between expression of TOPOIIα and resistance to doxorubicin (p<0.05). In conclusion, the expressions of the chemotherapy resistance related proteins of P-gp, MRP, LRP, GST-π and TOPOIIα in all the four types of human lung cancer cell lines were different. Their different expressions may lead to various chemosensitivity to cisplatin, doxorubicine and VP-16. GST-π was the most important mediator among the five proteins to predict the intrinsic resistance to cisplatin, TOPOIIα also could contribute, to certain degree, to the intrinsic resistance to doxorubicine and VP-16. Further investigation on the mechanism may be necessary for the research of chemotherapy resistance in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2769.
Objectives: A new method of determining protein turnover by labeling protein with 15N amino acids was used in conjunction with serum-free cell culture to profile secreted proteins that are released by MIA PaCa-2 pancreatic cancer cells in culture. Methods: MIA PaCa-2 cells were first cultured in Dulbecco modified Eagle medium (Gibco by Invitrogen, Carlsbad, Calif) with 10% fetal bovine serum, then in serum-free modified Eagle medium with or without 50% 15N algal amino acid mixture. The effect of oxythiamine chloride on secreteome was studied. Secreteome from cell culture media was analyzed by 2-dimensional (2D) gel electrophoresis. Differentially expressed proteins were detected and identified. Protein turnover rates were calculated according to the newly established method. Western blot and enzyme-linked immunosorbent assay were used to validate identified proteins. Results: Among the 14 differentially expressed proteins after oxythiamine treatment, tissue inhibitor of metalloproteases-1 and cytokeratin-10 were identified as 2 newly synthesized secreted proteins caused by substantial 15N incorporation. The inhibition of tissue inhibitor of metalloproteases-1 expression in MIA PaCa-2 cells by oxythiamine treatment was first demonstrated by 2D gel electrophoresis and further validated by Western blotting and enzyme-linked immunosorbent assay analyses. Conclusions: Our method of labeling protein with 15N amino acids in conjunction with serum-free cell culture allows the identification of actively secreted proteins from pancreatic cancer cells and is a useful method for serum biomarker discovery.
Pancreatic cancer (PC) is a devastating malignant tumor with high incidence and mortality rate worldwide. Meanwhile, the surgical approaches and drugs of this disease remain challenging. In recent years, reactive oxygen species (ROSs) study has become a hotspot in the field of PC research. ROSs may regulate tumor mic roenvironment (TME), cancer stem cells (CSCs) renewal and epithelial-mesenchymal transition (EMT), which result in drug-resistance and recurrence of the PC. Currently, TME that includes immune infiltrates, fibroblasts, vascular vessels and extracellular matrix has become a hotspot in the cancer research. Meanwhile, numerous researches have shown that ROSs-mediated TME plays a central role in the occurrence and development of PC. Targeting ROSs may be promising therapeutic treatments for the PC patients. Therefore, the purposes of the review were manifold: (1) to summarize the regulations of ROSs in tumorigenesis and drug-resistance of PC; (2) to investigate the modulation of ROSs in signaling cascades in PC; (3) to study the effects of ROSs in stromal cells in PC; (4) to generalize the potent therapies targeting ROSs in PC. Overall, this review summarized the current status of ROSs in PC research and suggested some potential anti-PC drugs that may target ROSs.
The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.
Liver injuries after blunt abdominal trauma are very common. Non-operative approaches to management are now the standard of care for many patients with up to and including grade V liver injuries. However, the long-term complications associated with coil embolization can be challenging to manage. We present the case of a 29-year-old male who presented with a chronic liver abscess which contained the coils following embolization of a grade IV liver injury and the subsequent transhepatic embolization of the pseudoaneurysm. In addition, the patient developed a fistula draining the abscess through the previously placed drain site that traversed the diaphragm. A multidisciplinary discussion was held between trauma surgery, hepatobiliary surgery, thoracic surgery, and interventional radiology to discuss the best treatment plan. The patient subsequently underwent liver resection, fistula tract resection, and diaphragm repair. This case presents a definitive management strategy for these complex patients.
Pancreatic ductal adenocarcinoma (PDAC) is universally acknowledged as the cancer with the highest mortality rate. Berberine has high medicinal value and has been used as an anti-cancer agent. Hence the purpose of this study was to investigate the anti-cancer effect of berberine in PDAC. Berberine was shown to have a selective anti-cancer effect on PDAC by MTT assay in vitro. Pancreatic cancer stem cells (PCSCs), regulated by epithelial–mesenchymal transition (EMT), could promote the proliferation of PDAC cells. However, berberine suppressed the proliferation and stemness of PCSCs through immunofluorescence staining, stem cell sphere assays and so forth in vitro. In vivo, berberine reduced tumor size and decreased the expression levels of Ki67, a marker of cellular proliferation, in orthotopic pancreatic tumors. In addition, berberine inhibited the EMT signaling pathway by RT-PCR and Western blotting methods both in vitro and in vivo. Our study indicates that berberine inhibits the proliferation of PDAC cells both in vivo and in vitro. The mechanism of the anti-cancer effect of berberine likely involves the inhibition of EMT. Therefore, berberine may be a novel antineoplastic drug with clinical efficacy in PDAC.
Abstract To understand how microRNAs (miRNAs) regulate breast cancer tumorigenesis, a miRNA expression microarray screening was performed using RNAs from formalin-fixed paraffin-embedded (FFPE) breast tissues, which included benign (n=13), ductal carcinoma in situ (DCIS) (n=16), and invasive ductal carcinoma (IDC) (n=15). Twenty miRNAs that were differentially expressed (p<0.01) were identified, of which let-7 family miRNAs were down-regulated in human breast cancer tissues at stages of DCIS and IDC compared to benign stage. To understand the role of let-7 miRNAs further, we performed bioinformatics analysis and found that let-7 miRNA sequences match sequences in the 3’-UTRs of estrogen receptor alpha 66 (ER-α66) and another novel receptor ER-α36. The targeting of let-7 miRNAs on ER-α66 and ER-α36 was further confirmed by a number of experimental assays, including luciferase assay, protein expression, and mRNA expression. Overexpression of let-7 miRNAs in ER-α66-positive breast cancer MCF7 cell line negatively affected ER-α66 mediated genomic estrogen pathway. As expected, down-regulation of the ER-α66 signaling by let-7 miRNAs inhibited cell proliferation, and subsequently triggered the cell apoptotic process in MCF7 cells. On the other hand, overexpression of let-7 miRNAs in ER-α66-negative cell line MB-MDA-231 negatively affected ER-α36 mediated non-genomic estrogen pathway. Besides, down-regulation of let-7 is correlated with up-regulation of ER-α36 in tamoxifen (Tam) and ICI-182780 (ICI) resistance in MCF7 cell line. Forced overexpression in Tam-and ICI-resistant MCF7 cells dampened ER-α36 expression. In conclusion, our findings not only indicate a new regulatory mechanism of let-7 miRNAs in ER mediated cellular malignant growth of breast cancer, and but also provide potential biomarkers and/or surrogate therapeutic targets useful for early diagnosis and/or therapeutic options for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2025.
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