PubMed | Korea Polytechnic University, Chonnam National University, Jeonnam Biofood Technology Center, Zhengzhou University and 3 more.
Type: Journal Article | Journal: International journal of oncology | Year: 2015
The World Health Organization (WHO) has reported that cancer is one of the most prevalent diseases and a leading cause of death worldwide. Many anticancer drug development studies have been pursued over the last few decades and several viable drugs have been discovered, such as paclitaxel, topotecan and irinotecan. Previously, our research group uncovered the cytocidal and cytostatic effects of the plant Stephania delavayi Diels. In this study, we determined the active chemical to be 6,7-di-O-acetylsinococuline (FK-3000). The FK-3000 half maximal inhibitory concentration (IC50) in MDA-MB-231 breast carcinoma cells at 48 h was 0.52 g/ml and it induced apoptosis in a dose- and time-dependent manner. FK-3000 suppressed NF-B nuclear translocation, decreased NF-B phosphorylation, and decreased COX-2 protein expression. MDA-MB-231 xenografted mice were treated with FK-3000, Taxol, or their combination for 21 days. The tumor size was smallest in the co-treatment group, indicating that FK-3000 may have a synergistic effect with Taxol. FK-3000 treatment showed no adverse effects on blood cell counts, serum protein levels, or pathology. These studies demonstrate that FK-3000, isolated from S. delavayi Diels., is a promising, pathway-specific anticancer agent that exhibits low toxicity.
PubMed | University of Michigan, Tianjin Medical University, Comparative Biomedicine Research Branch, CAS Shanghai Institute of Materia Medica and 2 more.
Type: Journal Article | Journal: Pharmaceutical research | Year: 2016
To investigate the applicability of fusion biotoxins combining pore-forming toxins (PFTs) and ribosome-inactivating proteins (RIPs) for the anti-cancer treatment.Membrane active PFTs tend to destabilize cell membranes of tumor cells, but lack a warhead inducing significant cause of cell death. Cell-impermeable RIPs possess a powerful warhead, yet not able to enter the tumor cells. To address these challenges for anti-tumor effects, we introduced a fusion strategy of conjugating melittin (a PFT) and gelonin (a type 1 RIP) via chemical and recombinant methods, followed by in vitro assays and in vivo animal studies.In vitro characterization results confirmed that the chimeric gelonin-melittin fusion proteins retained equivalent intrinsic activity to that of unmodified gelonin in inhibiting protein translation. However, chemically conjugated gelonin-melittin (cGel-Mel) and recombinant chimeric gelonin-melittin fusion (rGel-Mel) exhibited greater cell uptake, yielding a significantly enhanced cytotoxic activity over treatment of gelonin, melittin or physical mixture of gelonin and melittin. Remarkably, cGel-Mel and rGel-Mel displayed 32- and 10-fold lower IC50 than gelonin in the cell lines. The superior anti-tumor efficacy of multivalent cGel-Mel to monovalent rGel-Mel suggested that valency could be a crucial factor for the extent of melittin-mediated cell uptake. Tumoricidal effects observed from animal studies were in good accordance with our findings from the cellular assays.This study successfully demonstrated that fusion of biotoxins could provide a simple yet effective way to synergistically augment their anti-tumor activity.
PubMed | National Health Research Institute, Chungnam National University and Comparative Biomedicine Research Branch
Type: Journal Article | Journal: Molecules and cells | Year: 2016
Although innate color preference of motile organisms may provide clues to behavioral biases, it has remained a longstanding question. In this study, we investigated innate color preference of zebrafish larvae. A cross maze with different color sleeves around each arm was used for the color preference test (R; red, G; green, B; blue, Y; yellow). The findings showed that 5 dpf zebrafish larvae preferred blue over other colors (B > R > G > Y). To study innate color recognition further,
PubMed | University of Ulsan, A-Life Medical and Comparative Biomedicine Research Branch
Type: | Journal: Scientific reports | Year: 2016
Macroautophagy (autophagy) is believed to maintain energy homeostasis by degrading unnecessary cellular components and molecules. Its implication in regulating cancer metabolism recently started to be uncovered. However, the precise roles of autophagy in cancer metabolism are still unclear. Here, we show that autophagy plays a critical role in glutamine metabolism, which is required for tumor survival. Pancreatic ductal adenocarcinoma (PDAC) cells require both autophagy and typical glutamine transporters to maintain intracellular glutamine levels. Glutamine deprivation, but not that of glucose, led to the activation of macropinocytosis-associated autophagy through TFEB induction and translocation into the nucleus. In contrast, glutamine uptake increased as a compensatory response to decreased intracellular glutamine levels upon autophagy inhibition. Moreover, autophagy inhibition and glutamine deprivation did not induce cell death, while glutamine deprivation dramatically activated apoptotic cell death upon autophagy inhibition. Interestingly, the addition of -ketoglutarate significantly rescued the apoptotic cell death caused by the combination of the inhibition of autophagy with glutamine deprivation. Our data suggest that macropinocytosis-associated autophagy is a critical process providing glutamine for anaplerosis of the TCA cycle in PDAC. Thus, targeting both autophagy and glutamine metabolism to completely block glutamine supply may provide new therapeutic approaches to treat refractory tumors.
Lee E.J.,Comparative Biomedicine Research Branch |
Yun U.-J.,Comparative Biomedicine Research Branch |
Koo K.H.,Comparative Biomedicine Research Branch |
Sung J.Y.,Center for Pediatric Oncology |
And 4 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014
Lipid rafts, plasma membrane microdomains, are important for cell survival signaling and cholesterol is a critical lipid component for lipid raft integrity and function. DHA is known to have poor affinity for cholesterol and it influences lipid rafts. Here, we investigated a mechanism underlying the anti-cancer effects of DHA using a human breast cancer cell line, MDA-MB-231. We found that DHA decreased cell surface levels of lipid rafts via their internalization, which was partially reversed by cholesterol addition. With DHA treatment, caveolin-1, a marker for rafts, and EGFR were colocalized with LAMP-1, a lysosomal marker, in a cholesterol-dependent manner, indicating that DHA induces raft fusion with lysosomes. DHA not only displaced several raft-associated onco-proteins, including EGFR, Hsp90, Akt, and Src, from the rafts but also decreased total levels of those proteins via multiple pathways, including the proteasomal and lysosomal pathways, thereby decreasing their activities. Hsp90 overexpression maintained its client proteins, EGFR and Akt, and attenuated DHA-induced cell death. In addition, overexpression of Akt or constitutively active Akt attenuated DHA-induced apoptosis. All these data indicate that the anti-proliferative effect of DHA is mediated by targeting of lipid rafts via decreasing cell surface lipid rafts by their internalization, thereby decreasing raft-associated onco-proteins via proteasomal and lysosomal pathways and decreasing Hsp90 chaperone function. © 2013 Elsevier B.V.
Koo K.H.,Comparative Biomedicine Research Branch
Cell death & disease | Year: 2013
Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APC(Cdh1)-Skp2-p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance.
Sung J.Y.,Center for Pediatric Oncology National Cancer Center |
Park S.-Y.,National Cancer Center |
Kim J.H.,National Cancer Center |
Kang H.G.,National Cancer Center |
And 4 more authors.
Cell Death and Disease | Year: 2014
Interferon consensus sequence-binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-c) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial-to-mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-c treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knockdown. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP upregulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the upregulation of Snail. Knockdown of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Upregulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF-β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r=0.47, P=0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-b and Snail signaling pathways. © 2014 Macmillan Publishers Limited.
Cheong H.,Comparative Biomedicine Research Branch
Archives of Pharmacal Research | Year: 2015
Autophagy is a catabolic process mediated by lysosomal degradation and is a key player in regulating cellular metabolism during cancer progression. Autophagy maintains cellular homeostasis by degrading unnecessary cellular molecules, which also prevents tumorigenesis. Conversely, autophagy also provides nutrients that support malignant tumor growth in advanced tumors. Multiple novel mechanisms have been proposed to explain the tumor-facilitating role of autophagy. Autophagy regulates diverse metabolic pathways that promote tumor proliferation and survival, which are closely associated with oncogenic activators and tumor suppressors. Autophagy has been implicated in cancer cell invasion and metastasis. Accordingly, autophagy has emerged as a tumor-promoting mechanism that facilitates cancer cell growth and survival. Mechanistic studies of autophagy during tumor progression may identify potential targets that can be utilized to disrupt cancer development. Understanding the molecular networks integrating metabolic changes and autophagy in cancer cells could provide novel insights to enhance targeted cancer therapies. © 2015 The Pharmaceutical Society of Korea.
Sung S.,Comparative Biomedicine Research Branch |
Choi J.,Comparative Biomedicine Research Branch |
Cheong H.,Comparative Biomedicine Research Branch
Oncotarget | Year: 2015
Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrientdeprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues.
PubMed | Comparative Biomedicine Research Branch
Type: Journal Article | Journal: Oncotarget | Year: 2015
Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrient-deprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues.