Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038187 (starvation)
24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adenomatous polyposis coli (APC) tumor suppressor is a nucleocytoplasmic protein. The nuclear accumulation of APC was recently found to vary depending on cell density, suggesting that putative APC function(s) in the nucleus is controlled by the establishment of cell contacts. We report here that the density-dependent redistribution of APC between nucleus and cytoplasm prevails in 6/6 thyroid and colorectal carcinoma cell lines. Moreover, mutated APC lacking known nuclear localization sequences had the similar distribution pattern as the full-length protein. APC invariably accumulated in the nuclei of Ki-67 expressing cells, but was largely cytoplasmic when cell cycle exit was induced by serum starvation or at high cell density. APC colocalized with beta-catenin in the nucleus only in one cell line (SW480). Also, APC maintained a predominantly nuclear position in early confluent states when cytoplasmic beta-catenin was recruited to newly formed adherens-like junctions. The results indicate that nuclear targeting of APC is driven by cell cycle entry rather than altered cell-cell contact. The ability of C-terminally truncated APC to accumulate in the nucleus suggests that nuclear import signals other than NLS1(APC) and NLS2(APC) are functionally important. Residual function(s) of N-terminal APC fragments in tumor cells carrying APC mutations might be beneficial to tumor growth and survival.
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PMID:Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation. 1295 80

Activation of telomerase, which stabilizes the telomere length of chromosomes, is crucial for the continued growth or progression of cancer cells. In a previous study, we showed that telomerase is frequently activated in skin tumors. Because epidermal growth factor plays an important role during the tumorigenesis of epithelial tissue, we have now examined the role of epidermal growth factor signaling in regulating telomerase activity using HSC-1 human cutaneous squamous cell carcinoma cells. Treatment of HSC-1 cells with AG 1478, an inhibitor of the epidermal growth factor receptor, or with a neutralizing antibody to the epidermal growth factor receptor, significantly suppressed their telomerase activity, in association with inhibiting their growth. The suppression of telomerase activity was obvious at day 3 and was maximal at day 5 after treatment with AG 1478. The suppression of telomerase activity correlated with the decreased expression of human telomerase catalytic subunit (hTERT) mRNA, the rate-limiting determinant of its enzyme activity. The expression of c-Myc and of Sp1 proteins, transcription factors for hTERT, were also suppressed by AG 1478 in HSC-1 cells, but the expression of Ets-2 protein, another transcription factor, was not affected. The expression of Mad-1, a competitor of c-Myc, was increased. Inhibition of ERK, Src, or Akt suppressed telomerase activity in HSC-1 cells, but to a lesser extent than did treatment with AG 1478. Serum starvation suppressed telomerase activity, but addition of epidermal growth factor or transforming growth factor alpha did not increase it, indicating the involvement of other epidermal growth factor receptor ligands in the activation of telomerase in HSC-1 cells. These data indicate that blockade of the epidermal growth factor receptor might be effective in inhibiting telomerase activity of squamous cell carcinomas, which would lead to the suppression of tumor growth.
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PMID:Inhibition of the epidermal growth factor receptor suppresses telomerase activity in HSC-1 human cutaneous squamous cell carcinoma cells. 1470 11

AMP-activated protein kinases (AMPKs) are a class of serine/threonine protein kinases that are activated by an increase in intracellular AMP concentration. They are a sensitive indicator of cellular energy status and have been found to promote tumor cell survival during nutrient starvation. We recently identified a novel AMPK catalytic subunit family member, ARK5, whose activation is directly regulated by Akt, which, in turn, has been reported to be a key player in tumor malignancy. In this study, we attempted to determine whether ARK5 is involved in tumor malignancy under regulation by Akt. Matrigel invasion assays demonstrated that both overexpressed and endogenous ARK5 showed strong activity dependent on Akt. In addition, ARK5 expression induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 following new expression of membrane type 1 MMP (MT1-MMP), and the MT1-MMP expression induced by ARK5 was initiated by rapamycin-sensitive signaling. In nude mice, ARK5 expression was associated with a significant increase in tumor growth and significant suppression of necrosis in tumor tissue. Interestingly, only the ARK5-overexpressing PANC-1 cell line (P/ARK) tumor showed invasion and metastasis in nude mice, although Akt was activated in tumors derived from both P/ARK and its parental cell line. We report that a novel AMPK catalytic subunit family member, ARK5, plays a key role in tumor malignancy downstream of Akt.
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PMID:ARK5 is a tumor invasion-associated factor downstream of Akt signaling. 1506 Jan 71

Feline vaccine-associated sarcoma (VAS) is a biologically aggressive soft-tissue sarcoma that can develop at sites where inactivated feline vaccines have been administered. We showed that platelet-derived growth factor (PDGF) and its receptor (PDGFR) play a role in the growth of VAS cells. The presence of PDGFR-beta was confirmed in each of five VAS cell lines evaluated, one non-vaccine-associated feline fibrosarcoma (FSA) cell line and a feline fibroblast-derived cell line. The PDGF/PDGFR signaling pathway was inhibited in the VAS cell lines and the FSA cell line using the tyrosine kinase inhibitor imatinib mesylate (formerly called STI-571). Imatinib inhibited PDGF-BB-induced autophosphorylation of PDGFR in VAS cells and feline FSA cells in vitro in a dose-dependent manner. Imatinib also significantly inhibited growth of feline VAS tumors in a murine xenograft model. Imatinib reversed the protective effect of PDGF-BB on growth inhibition by doxorubicin and carboplatin. PDGF-BB protected VAS cells from serum starvation and doxorubicin-induced apoptosis but not carboplatin-induced apoptosis, and imatinib eliminated this protection. These observations suggest that imatinib inhibits PDGFR tyrosine kinase activity in feline soft tissue sarcomas in vitro and inhibits tumor growth in a xenograft model.
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PMID:Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. 1510 21

Both tolerance to nutrient starvation and angiogenesis are essential for cancer progression because of the insufficient supply of nutrients to tumor tissue. Since chronic nutrient starvation seldom occurs in normal tissue, cancer's tolerance to nutrient starvation should provide a novel target for cancer therapy. In this study, we propose an anti-austerity strategy to exploit the ability of agents to eliminate cancer cells' tolerance to nutrient starvation. We established a simple screening method for agents that inhibit cancer cell viability preferentially during nutrient starvation, using PANC-1 cell line cultured in nutrient-rich and nutrient-deprived media. After screening over 2000 culture media of actinomycetes, we identified a new compound, kigamicin D (C(48)H(59)NO(19)), which shows preferential cytotoxicity to cancer cells under nutrient-deprived conditions, but hardly any cytotoxicity under nutrient-rich conditions. Both subcutaneous and oral administration of kigamicin D strongly suppressed the tumor growth of several tested pancreatic cancer cell lines in nude mice. Moreover, kigamicin D was observed to block the activation of Akt induced by nutrient starvation. Therefore, our results suggest that kigamicin D be a candidate for implementing our novel concept, anti-austerity, which may serve as a new strategy for cancer therapy.
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PMID:Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy targeting cancer cells' tolerance to nutrient starvation. 1518 38

Voltage-dependent large-conductance Ca(2+)-activated K(+) channels, often referred to as BK channels, are a unique class of ion channels coupling intracellular chemical signaling to electrical signaling. BK channel expression has been shown to be up-regulated in human glioma biopsies, and expression levels correlate positively with the malignancy grade of the tumor. Glioma BK channels (gBK) are a splice variant of the hslo gene, are characterized by enhanced sensitivity to [Ca(2+)](i), and are the target of modulation by growth factors. By using the selective pharmacological BK channel inhibitor iberiotoxin, we examined the potential role of these channels in tumor growth. Cell survival assays examined the ability of glioma cells to grow in nominally serum-free medium. Under such conditions, BK channel inhibition by iberiotoxin caused a dose- and time-dependent decrease in cell number discernible as early as 72 hr after exposure and maximal growth inhibition after 4-5 days. FACS analysis shows that IbTX treatment arrests glioma cells in S phase of the cell cycle, whereupon cells undergo cell death. Interestingly, IbTX effects were nullified when cells were maintained in 7% fetal calf serum. Electrophysiological analysis, in conjunction with biotinylation studies, demonstrates that serum starvation caused a significant translocation of BK channel protein to the plasma membrane, corresponding to a two- to threefold increase in whole-cell conductance, but without a change in total gBK protein. Hence, expression of functional gBK channels appears to be regulated in a growth-factor-dependent manner, with enhanced surface expression promoting tumor cell growth under conditions of growth factor deprivation as might occur under in vivo conditions.
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PMID:Role for calcium-activated potassium channels (BK) in growth control of human malignant glioma cells. 1537 15

Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had approximately 1.2 days doubling time with loss of contact inhibition. All retained 1,25-(OH)(2) vitamin D(3)-induced expression of osteoblastic markers: collagen type I, alkaline phosphatase, and osteocalcin. All shared INK4a/ARF gene locus deletion and epigenetic silencing of the DBCCR1 tumor suppressor gene. Despite in vitro commonality, only four of six clones shared the growth kinetics and 100% tumorigenicity of the parental population. In contrast, one clone consistently formed latent tumors and the other established tumors with only 30% penetrance. Changing the in vitro microenvironment to mimic in vivo growth aspects revealed concordant clonal heterogeneity. Latent tumor growth correlated with extracellular matrix entrapment of multicellular spheroids and high procollagen type III expression. Poor tumorigenicity correlated with in vitro serum dependence and high p27(Kip1) expression. Aggressive tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer.
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PMID:Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. 1583 42

The p53 protein arrests the cell cycle at the G1 phase when stabilized by the interaction between ribosomal proteins and HDM2 under growth-inhibitory conditions. Meanwhile, p53, when translocated to the mitochondria in response to cell death signals, induces apoptosis via transcription-independent mechanisms. In this report, we demonstrate that the mitochondrial ribosomal protein L41 (MRPL41) enhances p53 stability and contributes to p53-induced apoptosis in response to growth-inhibitory conditions such as actinomycin D treatment and serum starvation. An analysis of MRPL41 expression in paired normal and tumor tissues revealed lower expression in tumor tissue. Ectopic MRPL41 expression resulted in inhibition of the growth of cancer cells in tissue culture and tumor growth in nude mice. We discovered that MRPL41 protein is localized in the mitochondria, stabilizes the p53 protein, and enhances its translocation to the mitochondria, thereby inducing apoptosis. Interestingly, in the absence of p53, MRPL41 stabilizes the p27(Kip1) protein and arrests the cell cycle at the G1 phase. These results suggest that MRPL41 plays an important role in p53-induced mitochondrion-dependent apoptosis and MRPL41 exerts a tumor-suppressive effect in association with p53 and p27 (Kip1).
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PMID:Mitochondrial ribosomal protein L41 suppresses cell growth in association with p53 and p27Kip1. 1602 96

Recent analyses indicate that the expression of the Pim-1 protein kinase is elevated in biopsies of prostate tumors. To identify the mechanism by which the Pim kinases may affect the growth of prostate tumors, we expressed Pim-1, Pim-2, or a kinase-dead Pim-2 protein in human PC3 prostate cancer cells. On implantation of the transfectants in nude mice, the growth of the cells expressing Pim-1 or Pim-2 was significantly faster than the growth of the control cells transfected with the neomycin-resistant gene or the kinase-dead Pim-2 protein. When grown in medium, the doubling time of the Pim-1 and Pim-2 transfectants was faster (0.75 days) than that of the control cells (1.28 days). We, therefore, examined the ability of Pim to control the phosphorylation of proteins that regulate protein synthesis. On growth factor starvation or rapamycin treatment, the Pim-1 and Pim-2 transfectants maintained their ability to phosphorylate 4E-BP1 and S6 kinase, although this phosphorylation did not occur in the control-transfected PC3 cells. We have found that the cellular levels of c-Myc were elevated in the Pim-1 and Pim-2 transfectants under these conditions. The Pim-1 and Pim-2 transfectants have lower levels of serine/threonine protein phosphatase 2A (PP2A) activity and the alpha- and beta-subunit B56gamma of the PP2A phosphatase do not coimmunoprecipitate in these cells. Thus, the effects of Pim on PP2A activity may mediate the levels of c-Myc and the phosphorylation of proteins needed for increased protein synthesis. Both of these changes could have a significant impact on tumor growth.
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PMID:Pim family kinases enhance tumor growth of prostate cancer cells. 1612 40

Tumor cells generally proliferate rapidly and the demand for essential nutrients as well as oxygen always exceeds the supply due to the unregulated growth and the insufficient and inappropriate vascular supply. However, cancer cells show an inherent ability to tolerate extreme conditions, such as that characterized by low nutrient and oxygen supply, by modulating their energy metabolism. Thus, targeting nutrient-deprived cancer cells may be a novel strategy in anticancer drug development. Based on that, we established a novel screening method to discover anticancer agents that preferentially inhibit cancer cell viability under the nutrient-deprived condition. After screening 500 medicinal plant extracts used in Japanese Kampo medicine, we found that a CH(2)Cl(2)-soluble extract of Arctium lappa exhibited 100% preferential cytotoxicity under the nutrient-deprived condition at a concentration of 50 microg/mL with virtually no cytotoxicity under nutrient-rich condition. Further bioassay-guided fractionation and isolation led to the isolation of arctigenin as the primary compound responsible for such preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against nutrient-deprived cells at a concentration of 0.01 microg/mL. Furthermore, arctigenin was also found to strongly suppress the PANC-1 tumor growth in nude mice, as well as the growth of several of the tested pancreatic cancer cell lines, suggesting the feasibility of this novel antiausterity approach in cancer therapy. Further investigation of the mechanism of action of arctigenin revealed that the compound blocked the activation of Akt induced by glucose starvation, which is a key process in the tolerance exhibited by cancer cells to glucose starvation.
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PMID:Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation. 1645 35


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