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R Stjernholm

Publications and source records attributed to R Stjernholm.

9 recordsLinked to original sources
PubMed2000

Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia.

We have shown previously that insulin promotes phosphorylation and activation of farnesyltransferase and geranylgeranyltransferase (GGTase) II. We have now examined the effect of insulin on geranylgeranyltransferase I in MCF-7 breast cancer cells. Insulin increased GGTase I activity 3-fold and augmented the amounts of geranylgeranylated Rho-A by 18%. Both effects of the insulin were blocked by an inhibitor of GGTase I, GGTI-286. The insulin-induced increases in the amounts of geranylgeranylated Rho-A resulted in potentiation of the Rho-A-mediated effects of lysophosphatidic acid (LPA) on a serum response element-luciferase construct. Preincubation of cells with insulin augmented the LPA-stimulated serum response element-luciferase activation to 12-fold, compared with just 6-fold for LPA alone (p < 0.05). The potentiating effect of insulin was dose-dependent, inhibited by GGTI-286 and not mimicked by insulin-like growth factor-1. We conclude that insulin activates GGTase I, increases the amounts of geranylgeranylated Rho-A protein, and potentiates the Rho-A-dependent nuclear effects of LPA in MCF-7 breast cancer cells.

Alkyl and Aryl Transferases↗
PubMed2000

Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia.

To investigate the cause and effect relationship between hyperinsulinemia and the increased amounts of farnesylated p21Ras, we performed hyperinsulinemic euglycemic clamps in normal weight volunteers as well as in normal mice and dogs. Insulin infusions significantly raised the amounts of farnesylated p21Ras in the white blood cells of humans, in liver samples of mice and dogs, and in aorta samples of mice. Obese hyperinsulinemic individuals and dogs (made hyperinsulinemic by surgical diversion of the pancreatic outflow from the portal vein into the vena cava) displayed increased amounts of farnesylated p21Ras before the hyperinsulinemic clamps. Infusions of insulin did not alter the already increased levels of farnesylated p21Ras in these experimental models. To further investigate the role of acquired insulin resistance in modulating insulin's effect on p21Ras prenylation, we induced insulin resistance in rats by glucosamine infusion. Insulin-resistant glucosamine-treated animals displayed significantly increased farnesylated p21Ras in response to insulin infusion compared to that in control saline-treated animals. Transgenic models of insulin resistance (heterozygous insulin receptor substrate-1 knockout mice, A-ZIP/F-1 fatless mice, and animals overexpressing glutamine:fructose-6-phosphate amidotransferase) contained increased amounts of farnesylated p21Ras. We conclude that hyperinsulinemia, either endogenous (a prominent feature of insulin resistance) or produced by infusions of insulin, increases the amounts of farnesylated p21Ras in humans, mice, and dogs. This aspect of insulin action may represent one facet of the molecular mechanism of the potentially detrimental influence of hyperinsulinemia.

Adult↗
PubMed1988

Preliminary evaluation of platinum transferrin (MPTC-63) as a potential nontoxic treatment for breast cancer.

Transferrin receptors on proliferating and malignant cells are well documented. Faulk et al. demonstrated transferrin receptors in breast carcinoma by immunofluorescence. Malignant cells requiring more iron modulate a transferrin receptor and the iron transporting protein transferrin delivers iron to the cell. We have developed a physiologically active platinum transferrin complex that has been tested on several cell lines in culture, a tumor model in the Fischer rat, and five human patients with advanced breast carcinoma. The complex slowed the rate of growth of feline lymphoma cells to one-half that of controls and killed human HeLa cell cultures in 7 days. Growth of the rat tumor was slightly impaired, but treated rats never got systemic disease and controls died. Two patients had dramatic responses to treatment. One had systemic disease and the other advanced locoregional disease. Both patients were on Tamoxifen, as receptors were positive for estrogen. Disease was progressing in the former with little improvement in the latter. After treatment both had a marked response. We postulate that MPTC-63 may work synergistically with Tamoxifen and be an effective nontoxic antitumor agent. More studies are indicated.

Animals↗
PubMed1978

Binding of platinum to human transferrin.

A complex of platinum and human transferrin has been formed by appropriately combining apotransferrin (metal free protein) and potassiumchloroplatinate (K2PtCl4). Atomic absorption spectroscopy indicated that both primary bind sites on the protein participated in the complex. Electron paramagnetic resonance (EPR) examination showed that the bound platinum was not paramagnetic, and thus it is highly probable that the Pt ion is in the +2 oxidation state. The results suggest a possible mechanism for physiological distribution of third-transition-series metals.

Chemical Phenomena↗
PubMedDate not supplied

Electron paramagnetic resonance investigation of high-spin iron (III) in cancer.

The concentration of iron (III)-transferrin (IT) in whole blood and serum, along with another high-spin (five unpaired electrons) iron complex (probably IT) accumulated by tumor tissue, was investigated by electron paramagnetic resonance (EPR) spectroscopy during the development of Murphy-Sturm rat lymphosarcoma. The observed changes in concentration (microgram/ml) of IT in sera/blood were generally complementary to those from tissue and the character of the modifications suggested the existence of three distinct phases of systemic response to the implantation: (1) an initial response, evidenced by a sharp reduction in serum IT and somewhat high tissue-IT concentration (microgram/g); (2) a period in which the tumor is (2) a period in which the tumor is becoming established, indicated by relatively constant tissue IT levels and near normal serum IT; and (3) the onset of rapid cell multiplication, characterized by increased total tissue-IT accumulation that rises to above 200% of normal available serum iron, increasing tissue-IT concentration, and rapidly declining serum-IT concentration. The results suggest that, in the face of an implanted tumor there are two detectable abnormal serum-IT responses: (1) an initial change, probably due to systemic blockage of iron reutilization; and (2) extraction of IT from serum by multiplying tumor cells, which is probably a major contributor to reduced serum-IT levels and ultimately anemia.

Animals↗