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Transformation of rat intestinal epithelial cells by overexpression of Rab25 is microtubule dependent.

ABSTRACT: Little research has addressed the role of membrane trafficking and recycling in the regulation of the transformed phenotype of neoplastic cells. The small GTPase Rab25 is an epithelial-specific modulator of membrane recycling. Recent studies have demonstrated that Rab25 expression is up-regulated in a number of epithelial cancers and overexpression may increase the aggressive phenotype of certain cancers. We have utilized the nontransformed RIE cell line to examine the influence of Rab25 on transformation. Overexpression of Rab25 in RIE cells leads to morphological transformation as well as growth in soft agar, tumor formation in nude mice, disruption of integrin-based focal adhesions, and alteration in modified microtubule subsets. Although the predominance of recent cancer research has focused on the manipulation of the actin-based cytoskeleton, recycling trafficking relies on microtubules. Transformation of RIE cells through overexpression of Rab25, but not with H-Ras(V12) , was reversed by inhibitors of microtubule polymerization. These results suggest that up-regulation of Rab25 in RIE cells leads to microtubule-dependent transformation. Thus, depolymerization of microtubules may be a potent therapeutic target for cancer therapy through the reversal of the invasive phenotype of certain cancer cells.

SUBMITTER: Lapierre LA

PROVIDER: S-EPMC3885764 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Transformation of rat intestinal epithelial cells by overexpression of Rab25 is microtubule dependent.

Lapierre Lynne A LA Caldwell Cathy M CM Higginbotham James N JN Avant Kenya M KM Hall Janine J Beauchamp R Daniel RD Goldenring James R JR

Cytoskeleton (Hoboken, N.J.) 20110103 2

Little research has addressed the role of membrane trafficking and recycling in the regulation of the transformed phenotype of neoplastic cells. The small GTPase Rab25 is an epithelial-specific modulator of membrane recycling. Recent studies have demonstrated that Rab25 expression is up-regulated in a number of epithelial cancers and overexpression may increase the aggressive phenotype of certain cancers. We have utilized the nontransformed RIE cell line to examine the influence of Rab25 on tran ...[more]

PMID: 21246754

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Project description:BackgroundChronic alcohol use often leads to malnutrition. However, how the intestinal absorption of nutrients such as glucose may be affected during moderate ethanol use has not been investigated. Glucose is absorbed via sodium (Na)-dependent glucose co-transport (SGLT1; SLC5A1) along the brush border membrane (BBM) of intestinal absorptive villus cells.ObjectiveThe aim of this study was to investigate how moderate alcohol consumption affects the absorption of glucose via SGLT1.MethodsIntestinal epithelial cells (IEC-18; rat) were exposed to 8.64 mM ethanol over 1, 3, 6, and 12 h. Rats (16-wk-old, male, Sprague-Dawley) were administered 2 g/kg ethanol over 1, 3, and 6 h. Na-dependent 3H-O-methyl-d-glucose uptake was measured to assess SGLT1 activity. Na-K-ATPase activity was measured as a function of inorganic phosphate release. Protein expression was analyzed by Western blot analysis and immunohistochemical staining.ResultsEthanol significantly decreased Na-dependent glucose absorption in enterocytes in vitro (ethanol treatment: 48.4% of controls at 1 h; P < 0.01) and in vivo (ethanol treatment: 60.0% of controls at 1 h; P < 0.01). Na-K-ATPase activity was significantly inhibited in vitro (ethanol treatment: 36.9% of controls at 1 h; P < 0.01) and in vivo (ethanol treatment: 42.1% of controls at 1 h; P < 0.01). Kinetic studies showed that the mechanism of inhibition of Na-glucose co-transport was secondary to a decrease in the affinity (1/Km) of the co-transporter for glucose both in vitro and in vivo. Western blots and immunohistochemistry further demonstrated unaltered amounts of SGLT1 after ethanol treatment.ConclusionsModerate ethanol significantly decreases glucose absorption in IEC-18 cells and in villus cells of Sprague-Dawley rats. The inhibition of SGLT1 is secondary to an altered Na gradient at the cellular level and secondary to diminished affinity of the co-transporter for glucose at the protein level in the BBM. These observations may, at least in part, explain 1 possible mechanism of the onset of malnutrition associated with alcohol consumption.

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Transformation of rat intestinal epithelial cells by overexpression of Rab25 is microtubule dependent.

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Transformation of rat intestinal epithelial cells by overexpression of Rab25 is microtubule dependent.

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