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)

Hyaluronan-binding sites were demonstrated on the cell surface of three malignant mesothelioma cell lines derived from human tumors using either [3H]hyaluronan or fluorescein-tagged hyaluronan. No hyaluronan-binding activity was observed on normal human mesothelial cells. The absence of hyaluronan receptors on normal human mesothelial cells was not due to a down-regulation by endogenously synthesized hyaluronan, since no binding sites appeared when the cells were cultured under conditions known to suppress hyaluronan synthesis (in starvation medium containing either hydrocortisone or n-butyrate) or to degrade endogenously synthesized hyaluronan (in the presence of Streptomyces or testicular hyaluronidase). The binding of [3H]hyaluronan on mesothelioma cells could be partially inhibited by prior incubation of the cells with trypsin, indicating that the hyaluronan-binding site is a protein. The binding sites on human malignant mesothelioma cells were shown to be saturable with about 54,000 hyaluronan molecules (M(r) 1.4 x 10(6)) bound per cell with a Kd of 0.3 x 10(-9) M. The binding was specific for hyaluronan inasmuch as a number of other macromolecules gave negligible inhibition of the binding. High molecular weight preparations of hyaluronan inhibited the binding more effectively than low molecular weight preparations; hyaluronan oligosaccharides down to a length of six monosaccharide units showed competing activity. The hyaluronan receptor appeared to be related to CD44 (a cell surface glycoprotein previously suggested to function as a hyaluronan receptor) since Hermes-1 monoclonal antibodies which inhibit the binding of hyaluronan to CD44 blocked a major part of the binding of hyaluronan to the mesothelioma cells. However, there was no strict correlation between the hyaluronan-binding activity on the mesothelioma cell lines tested and the levels of CD44 molecules on their cell surface, suggesting that only a subfraction of the CD44 molecules bound hyaluronan or that other hyaluronan-binding proteins also exist on those cells. The presence of hyaluronan receptors on mesothelioma cells, but not on their normal counterparts, may be of importance for the migration of the transformed cells in hyaluronan-enriched matrices and for their ability to form metastases.
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PMID:Hyaluronan receptors are expressed on human malignant mesothelioma cells but not on normal mesothelial cells. 751 23

Clinical management of malignant mesothelioma (MM) is very challenging due to marked resistance of this tumor to chemotherapy. Various mechanisms lead to a less than ideal drug concentration inside of MM cells, diminishing cytotoxicity. Consequently, single cytotoxic drugs achieve very modest response rates in MM patients, and combination regimens using standard and novel therapies have achieved only limited improvement in overall survival. Here, we demonstrate that MYC has either proliferative or pro-survival effects in MM cells during normal or stressed conditions, respectively. A MYC inhibitor 10058-F4 reduced MM cell proliferation via down regulation of cyclin D. Under serum starvation conditions, MM cells became quiescent, and the addition of MYC inhibitors triggered apoptosis in the resting MM cells. We also found that high concentrations of the PAK inhibitor PF3758309 killed MM cells, but the drug had only cytostatic effects at lower concentrations. These quiescent cells underwent apoptosis upon pharmacological inhibition of MYC. A novel MYC inhibitor KJ-Pyr-9 and a newer PAK inhibitor, FRAX597, also demonstrated marked cytotoxic cooperativity. Collectively, these findings demonstrate that targeting of MYC can sensitize MM cells and provide rationale for inhibition of MYC and PAK as a novel combinatory regimen for the treatment of this otherwise therapy-resistant, clinically incurable malignancy.
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PMID:Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity. 2886 28

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose-starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m-chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.
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PMID:Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1. 3068 65