Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) regulate the structural integrity of the extracellular matrix (ECM). Constitutive expression of human TIMP-3 in human DLD colon carcinoma cells renewed serum-responses and inhibited tumour formation in nude mice. To elucidate the mechanism of TIMP-3-mediated tumour suppression, we compared parental DLD and TIMP-3 expressing DLD cells (TIMP-3/DLD), finding them to be significantly different. TIMP-3/DLD cultures have fewer mitotic cells, are delayed in G1, and die after serum starvation. TIMP-3/DLD conditioned media activates cell death on fibroblast cells. The cell death induced by serum starvation and conditioned media was inhibited by 70%, in the presence of neutralizing tumour necrosis factor alpha (TNF-alpha) antibody. TIMP-3/DLD whole cell lysate contained p55 TNF-alpha receptor, while vector/DLD lysate had p55 TNF-alpha receptor and p46 soluble TNF-alpha inhibitor. Vector/DLD conditioned media had p46, while no soluble TNF-alpha receptor was detected in TIMP-3/DLD conditioned media. In addition, FACS analysis revealed that TIMP-3/DLD cells have more TNF-alpha surface binding sites, suggesting a direct correlation between TIMP-3 expression and surface receptors. The mechanism of tumorigenic reversion induced by TIMP-3 in DLD cells may involve protection of receptors from the proteolytic activity of MMPs. Putative TIMP-3-mediated inhibition of MMPs restores the TNF-alpha p55 signalling pathway and the carcinoma cell is killed by autocrine TNF-alpha. Thus, DLD cells have specific ECM MMPs that cleave cytokines and cytokine receptors. TIMP-3 specifically inhibits MMPs involved in receptor shedding.
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PMID:TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells. 934 10

We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.
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PMID:Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. 1108 46

Sensitive-to-apoptosis gene (SAG)/regulator of cullins (ROC)2/Rbx2/Hrt2 is a newly identified component of SCF E3 ubiquitin ligase that controls cell-cycle progression by promoting ubiquitination and degradation of cell-cycle inhibitors. We recently found that SAG protects cells from apoptosis induced by redox agents, promotes S-phase entry and cell growth under serum starvation, and is required for yeast growth. In the present study, we report that the SAG protein level was elevated in six of 10 human colon carcinoma tissues (60%) as compared with adjacent normal tissues from the same patient. SAG overexpression in preneoplastic cells in a JB6 tumor promotion-and-progression model did not induce neoplastic transformation, and SAG overexpression in NIH/3T3 cells did not induce transforming foci formation, suggesting that SAG is not a dominant oncogene. However, when DLD-1 human colon carcinoma cells were transfected with antisense SAG, monolayer growth was significantly inhibited, as shown by a decreased number of stable colonies in the plate after normalization with transfection efficiency. Stable clones that expressed antisense SAG showed a 50% decrease in their ability to form colonies when grown in soft agar versus clones that did not express antisense SAG. We found an inverse correlation in four of 10 tumors between the levels of SAG and p27, a cyclin-dependent kinase inhibitor. We concluded that SAG is not causally related to cellular transformation, but its overexpression may be important for the maintenance of tumor cell phenotype. Therefore, targeting SAG expression may have therapeutic value in cancer treatment. Mol. Carcinog. 30:62-70, 2001.
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PMID:Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth. 1125 65

Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1, 2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells. Kigamicin D inhibited tumor cell-induced angiogenesis in a dorsal air sac assay. On the basis of these results we tested other human tumor xenograft models and transplantable syngeneic tumor models in order to determine the spectrum of activity of kigamicin D against various cancers. Kigamicin D showed a weak antitumor effect against LX-1 and DMS-273 lung cancers, but had no effect on DLD-1 colon cancers. When tested against syngeneic tumors, kigamicin D showed a weak antitumor effect against colon26, but showed augmentation of tumor growth on IMC carcinoma at a broad dosage level. Kigamicin D does not show good antitumor activity against human xenograft tumors except pancreatic tumors and murine syngeneic tumors. We found that kigamicin D has excellent antitumor effect specific to pancreatic cancers. Surprisingly, high dosage of kigamicin D increased tumor growth of IMC carcinoma by than 200%. The phenomenon suggests that kigamicin D may cause some immunological response to the tumor.
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PMID:Antitumor effect of kigamicin D on mouse tumor models. 1683 Aug 87

Several types of cancer cells, including colorectal cancer-derived cell lines, show austerity, the resistance to nutrient starvation, but exactly how cancer cells obtain energy sources under conditions in which their external nutrient supply is extremely limited remains to be clarified. Because autophagy is a catabolic process by which cells supply amino acids from self-digested organelles, cancer cells are likely to use autophagy to obtain amino acids as alternative energy sources. Amino acid deprivation-induced autophagy was assessed in DLD-1 and other colorectal cancer-derived cell lines. The autophagosome-incorporated LC3-II protein level increased after treatment with a combination of autolysosome inhibitors, which interferes with the consumption of autophagosomes. Autophagosome formation was also morphologically confirmed using ectopically expressed green fluorescent protein-LC3 fusion proteins in DLD-1 and SW480 cells. These data suggest that autophagosomes were actively produced and promptly consumed in colorectal cancer cells under nutrient starvation. Autolysosome inhibitors and 3-methyl adenine, which suppresses autophagosome formation, remarkably enhanced apoptosis under amino acid-deprived and glucose-deprived condition. Similar results were obtained in the cells with decreased ATG7 level by the RNA interference. These data suggest that autophagy is pivotal for the survival of colorectal cancer cells that have acquired austerity. Furthermore, autophagosome formation was seen only in the tumor cells but not in the adjacent noncancerous epithelial cells of colorectal cancer specimens. Taken together, autophagy is activated in colorectal cancers in vitro and in vivo, and autophagy may contribute to the survival of the cancer cells in their microenvironment.
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PMID:Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. 1794 97

Glucose-related proteins (GRPs) are ubiquitously expressed in the endoplasmic reticulum and assist in protein folding and assembly, consequently considered to be molecular chaperones. GRP78 and GRP94 expression was induced by glucose starvation and up-regulated in samples taken from several different malignant tissues. To clarify the roles of both molecules in tumorigenesis and progression of colorectal carcinomas, immunohistochemistry (IHC) was performed on tissue microarrays containing colorectal carcinomas, adenomas and the non-neoplastic mucosa (NNM) using antibodies against GRP78 and GRP94. Their expression was correlated with the clinicopathological parameters of carcinomas. Both proteins were also studied in colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) by IHC and Western blot. There was a gradually increased GRP78 expression from colorectal NNMs, carcinomas, to low-grade and high-grade adenomas (P<0.05), while up-regulated GRP94 expression from NNM, low-grade adenoma, high-grade adenoma, to carcinoma (P<0.05). The expression was similar in all the carcinoma cell lines. GRP78 expression was negatively correlated with lymphatic invasion or low GRP94 expression of the carcinomas (P<0.05), while there was no correlation of GRP94 expression with other parameters of carcinomas (P>0.05). Multivariate analysis showed that venous invasion, lymph node metastasis and UICC staging (P<0.05), but not age, sex, tumor size, differentiation, depth of invasion, lymphatic invasion, GRP78 and GRP94 expression (P>0.05), were independent prognostic factors for carcinomas. It is suggested that up-regulated expression of GRP78 and GRP94 could possibly be involved in the pathogenesis of colorectal carcinomas.
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PMID:Overexpression of GRP78 and GRP94 is involved in colorectal carcinogenesis. 2147 81

Histone deacetylase (HDAC) overactivity in colorectal cancer (CRC) promotes cancer progression. In the current study, we showed that 4SC-202, a novel class I HDAC inhibitor (HDACi), potently inhibited survival and proliferation of primary human colon cancer cells and established CRC lines (HT-29, HCT-116, HT-15, and DLD-1). Yet, the same 4SC-202 treatment was non-cytotoxic to colon epithelial cells where HDAC-1/-2 expressions were extremely low. 4SC-202 provoked apoptosis activation in CRC cells, while caspase inhibitors (z-VAD-CHO and z-DVED-CHO) significantly alleviated 4SC-202-exerted cytotoxicity in CRC cells. Meanwhile, 4SC-202 induced dramatic G2-M arrest in CRC cells. Further studies showed that AKT activation might be an important resistance factor of 4SC-202. 4SC-202-induced cytotoxicity was dramatically potentiated with serum starvation, AKT inhibition (by perifosine or MK-2206), or AKT1-shRNA knockdown in CRC cells. On the other hand, exogenous expression of constitutively active AKT1 (CA-AKT1) decreased the sensitivity by 4SC-202 in HT-29 cells. Notably, 4SC-202, at a low concentration, enhanced oxaliplatin-induced in vitro anti-CRC activity. In vivo, we showed that oral gavage of 4SC-202 inhibited HT-29 xenograft growth in nude mice, and when combined with oxaliplatin, its activity was further strengthened. Together, these pre-clinical results indicate that 4SC-202 may be further investigated as a valuable anti-CRC agent/chemo-adjuvant.
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PMID:Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells. 2683 68