Cell cycle regulation of metallothionein in human colonic cancer cells.

Nagel, Wolfgang; Vallée, Bert L.

doi:10.1073/pnas.92.2.579

Cited by 138 publications

(63 citation statements)

References 64 publications

(55 reference statements)

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“…Using flow cytometry, the highest concentration of MT was found in cells at the end of G1 phase and at the threshold of G1/S phases [38]. Moreover, a significant MT translocation was immunocytochemically demonstrated to take place from cytoplasm to cell nucleus during S phase of cell cycle [3,15].…”

Section: Discussionmentioning

confidence: 92%

Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers.

Gomułkiewicz

Podhorska-Okołów²,

Szulc³

et al. 2010

Folia Histochem Cytobiol.

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Abstract:Our study aimed at examining significance of metallothionein (MT) expression in ductal breast cancers by determination of a relationship between expression of MT protein (MT-1/2) and selected prognostic factors, including grade of histological differentiation (G), expression of Ki-67 proliferative antigen, expression of estrogen receptors (ER) and progesterone receptors (PgR) and expression of HER-2 receptor. Material for the studies involved 54 samples of invasive ductal breast cancer, manifesting malignancy grades of G1-G3. In paraffin sections of examined tumours immunohistochemical reactions were performed using specific antibodies directed to MT, Ki-67, ER, PgR or HER-2. Intensity of MT-specific immunohistochemical reactions was measured using the semiquantitative IRS scale of Remmele. Intensity of colour reactions targeted at Ki-67, ER, PgR was evaluated scoring proportions of positive cells, while HER-2-specific reactions were evaluated in the scale of 0-3 points. The lowest level of MT expression was detected in breast cancer cases of G1 malignancy grade (G1 vs G3 p=0.020). A positive correlation between MT and Ki-67 antigen expression (r=0.32, p=0.019) was disclosed. Moreover, MT expression exhibited negative correlations with expression of ER (r=-0.35, p=0.008) and PgR (r=-0.27, p=0.046). No relationships could be detected between expression of MT and expression of HER-2 (r=0.12, p=0.37). The obtained results suggest that MT expression might be helpful in prognostic evaluation of ductal breast cancers. Abbreviations: MT -metallothionein; Ki-67 -proliferative antigen; ER -estrogen receptor; PgR -progesterone receptor; HER-2 -human epidermal growth factor receptor 2; G -grade of histological differentiation; IRS -immuno-reactive score

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Section: Discussionmentioning

confidence: 92%

Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers.

Gomułkiewicz

Podhorska-Okołów²,

Szulc³

et al. 2010

Folia Histochem Cytobiol.

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“…Nagel and Vallee (1995) reported that the level of MT during the mitotic cell cycle of human colon cancer cells reached its maximum near the G1/S boundary of the cell cycle, around the onset of DNA synthesis, raising a physiological role for MT in cell proliferation. Similarly, MT protein expression singly or in combination with PCNA expression was significantly associated with poor prognosis in oesophageal SCC in the univariate analysis, while, in the step-wise multiple regression test, neither MT expression nor PCNA could be an independent prognostic factor in oesophageal SCC.…”

Section: Discussionmentioning

confidence: 99%

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

et al. 1999

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Squamous cell carcinoma (SCC) of the oesophagus is well recognized for its aggressive biological behaviour, in respect of local infiltration and metastases to regional lymph nodes and distant organs (Orrigner, 1997). Extra-oesophageal tumour spread is present in 70% of cases at the time of diagnosis, and the 5-year survival is only 3% when lymph node metastases are present, compared with 42% in lymph node negative patients (Orrigner, 1997). Patients with distant metastasis also have a poor prognosis, with a 5-year survival rate of 5% or less (Mandard et al, 1984;Orrigner, 1997).Metastasis is a multistep process involving complex associations of tumour cells with host cells or with matrix (Stracke and Liotta, 1995). Recently, genetic mechanisms underlying metastasis and pathogenesis of oesophageal SCC have been explored in several studies: int-2/hst-1 co-amplification correlated with high incidence of metastasis in distant organs (Kitagawa et al, 1991), loss of heterozygosity of the DCC gene associated with the degree of lymph node metastasis (Miyake et al, 1994), and mutation of the p53 gene in the pathogenesis (Hollstein et al, 1990;Meltzer et al, 1991) of SCC. However, there are only a limited number of reports on the prognostic indicators for invasion and metastasis of oesophageal SCC.Metallothioneins (MTs) have been described in most vertebrate and invertebrate species as low molecular weight proteins. Overexpression of MT was described in a variety of human tumours, in relation to different stages of tumour development and progression (Jasani and Schmid, 1997). MT was considered as a potential prognostic marker in invasive ductal carcinoma of the breast by Schmid et al (1993) and others (Fresno et al, 1993;Goulding et al, 1995, Oyama et al, 1996. In skin carcinoma (Zelger et al, 1994), melanoma (Zelger et al, 1993), cervical carcinoma (Lim et al, 1996) and pancreatic carcinoma (Ohshio et al, 1996), MT overexpression appears to be predominantly associated with more advanced, highly malingant tumours. To the contrary, Öfner et al (1994) reported that MT overexpression in colorectal carcinoma was associated with better clinical outcome and tumour stages. Therefore, MT overexpression may be paradoxically associated in some tumours with better clinical outcome.Tumour MT level also has been reported to correlate with resistance to anticancer reagents (Kelley et al, 1988;Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995;Hishikawa et al, 1997). In oesophageal SCC, we already reported that MT protein expression might be a significant determinant of prognosis, in particular, associated with cisplatin resistance (Hishikawa et al, 1997). Patients with MT protein-negative tumours survived longer when treated with cisplatin than those with MT protein-positive tumours. However, the exact biological significance of the expression of MT protein and mRNA is largely unknown in the clinical setting of oesophageal SCC.Therefore, in the present study, we have investigated the expressions of both MT mRNA and its protein in...

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“…We wondered whether the arrest in G1 was causally related to the increase in PtdIns synthesis. To test the possibility that G1 arrest induced PtdIns synthesis, cells were treated with mevastatin, an inhibitor of HMG-CoA reductase, that has been shown to cause cell cycle arrest in G1 (18), and both DNA and phospholipid synthesis were monitored. Incorporation of radiolabeled thymidine into DNA is inhibited by 59%, yet no effect is seen on the incorporation of glycerol into either PtdCho or PtdIns (Fig.…”

Section: Effect Of G1 Arrest On Ptdins Synthesismentioning

confidence: 99%

Regulation of de novo phosphatidylinositol synthesis

Nuwayhid

Vega

Walden

et al. 2006

Journal of Lipid Research

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Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) synthesis in mammalian cells have not been elucidated. In this study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 h) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 h), a marked increase is observed. TPA-induced glucose uptake from the medium is not required for observation of the stimulation of PtdIns synthesis, because the effect is apparent in glucose-free medium. Inhibition of the activation of arachidonic acid substantially blocks the synthesis of PtdIns but has no effect on the synthesis of phosphatidylcholine (PtdCho). Increasing the concentration of cellular phosphatidic acid by blocking its conversion to diacylglycerol, on the other hand, enhances the synthesis of PtdIns and inhibits the synthesis of PtdCho. The TPA-induced stimulation of PtdIns synthesis is not the result of the concomitant TPA-induced G1 arrest, because G1 arrest induced by mevastatin has no effect on PtdIns synthesis. Inhibition of protein kinase C activity blocks the stimulatory action of TPA on de novo synthesis of PtdIns but has no effect on TPA-induced inhibition.Potential sites of enzymatic regulation are discussed.-Nuwayhid, S. J., M. Vega, P. D. Walden, and M. E. Monaco. Phosphatidylinositol (PtdIns) is an essential acidic phospholipid found in the membranes of mammalian cells (1) as well as on the chromatin (2). A single molecular species composed of stearate (R9) and arachidonate (R99) accounts for z80% of the total PtdIns. There are two pathways for the synthesis of PtdIns: the de novo pathway and the salvage pathway, which converge at the level of phosphatidic acid (PtdOH). The de novo pathway uses dihydroxyacetone phosphate derived from glucose to make glycerol phosphate, which is subsequently acylated at the sn-1 position with stearate and then at the sn-2 position with arachidonate to yield PtdOH. In the salvage pathway, diacylglycerol (DAG), derived from phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ), is converted to PtdOH through the action of DAG kinase. In the first instance, there is a net increase in PtdIns, whereas in the second, there is not. The central element of both pathways is the production of PtdOH. For the salvage pathway, it appears that the conversion of DAG to PtdOH by DAG kinase is stimulated as a result of agonist-induced polyphosphoinositide turnover. Whether this results from an increase in DAG substrate and/or an increase in DAG kinase enzyme activity is unclear. This laboratory has previously demonstrated that the two pathways can be differentiated in situ on the basis of the inhibition by triacsin C, a specific inhibitor of arachidonate-specific long-chain fatty acyl-CoA synthetase (ACSL4) in situ (3, 4).Although regulation of the salvage pathway via the activation ...

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Cell cycle regulation of metallothionein in human colonic cancer cells.

Cited by 138 publications

References 64 publications

Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers.

Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers.

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

Regulation of de novo phosphatidylinositol synthesis

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