Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated

Lin, Hung Yun; Tang, Heng Yuan; Keating, Travis; Wu, Yun; Shih, Ai; Hammond, Douglas; Sun, Mingzeng; Hercbergs, Aleck; Davis, Faith B.; Davis, Paul J.

doi:10.1093/carcin/bgm239

Cited by 114 publications

(179 citation statements)

References 22 publications

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“…10,11,14 That plasma membrane integrin αvβ3 regulates expression of a spectrum of genes, including several that are cell cycle-relevant, was shown by Mangale et al 15 in studies of the interaction of the integrin with a natural extracellular matrix protein ligand, vitronectin. Thus, both protein ligands and small molecule ligands of the integrin may affect the latter's ability to regulate gene expression.…”

Section: Discussionmentioning

confidence: 98%

Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac)

Glinskii¹,

Glinsky²,

Lin³

et al. 2009

Cell Cycle

110

126

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Section: Discussionmentioning

confidence: 98%

Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac)

Glinskii¹,

Glinsky²,

Lin³

et al. 2009

Cell Cycle

110

126

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“…Resveratrol binding to integrin a V b 3 (8) could account for the activation of ERK1/2 (42). As resveratrol induced a redistribution of the integrin a V b 3 as well as Akt, FAK, Fyn, and Ras proteins in lipid rafts, our data support that these microdomains may function as microcompartments for the assembly of signaling complexes (43).…”

Section: Discussionmentioning

confidence: 99%

“…8,9) and/or its ability to trigger tumor cell death by apoptosis (4,(10)(11)(12). There is also compelling evidence that resveratrol can sensitize tumor cells to various anticancer drugs (13,14) and cytokines such as TRAIL (11), possibly because of the clustering of death receptors in detergent-resistant membranes (DRM) known as lipid rafts (4,11,15).…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Colin

Limagne²,

Jeanningros³

et al. 2011

Cancer Prevention Research

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trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [ 3 H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5-20 mmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-b-cyclodextrin (2-12 mg/mL), nystatin (12 ng/mL), and filipin (1 mg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin-and cholesterol-enriched cell fractions. Interestingly, extracellular signalregulated kinases (ERK), c-Jun NH 2 -terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC 50 at 48 h % 30 mmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin a V b 3 (revealed by coimmunoprecipitation with an anti-integrin a V b 3 antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death.

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“…Human glioma U-87 MG cells (4,21,30,35) were purchased from ATCC (Rockville, MD) and maintained in EMEM supplemented with 10% FBS and incubated in a 95% air-5% CO 2 incubator at 37°C. Before treatment, cells were exposed for 2 days to 0.25% hormone-stripped FBS-containing medium.…”

Section: Methodsmentioning

confidence: 99%

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Lin¹,

Sun²,

Tang³

et al. 2009

American Journal of Physiology-Cell Physiology

234

236

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,5,3Ј-Triiodo-L-thyronine (T3), but not L-thyroxine (T4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an ␣ v␤3 integrin receptor on human glioblastoma U-87 MG cells. Although both T 3 and T4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T 3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T 3 and T4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T 3-treated U-87 MG cells. T3 and T4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Smallinterfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T 3 on U-87 MG cells. PI3-kinase-dependent actions of T 3 in these cells included shuttling of nuclear thyroid hormone receptor-␣ (TR␣) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1␣ mRNA; LY-294002 inhibited these actions. Results of studies involving ␣v␤3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T3 from the integrin by unlabeled T3 and by unlabeled T4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T3 exclusively, activates PI3-kinase via Src kinase, and stimulates TR␣ trafficking and HIF-1␣ gene expression. Tetrac and RGD peptide both inhibit T3 action at this site. The second site binds T4 and T3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T3 action here is inhibited by tetrac alone, but the effect of T4 is blocked by both tetrac and the RGD peptide. thyroid hormone; phosphatidylinositol 3-kinase; extracellular signal-regulated kinase 1/2; integrin ␣v␤3; glioblastoma cells; Src kinase; mitogenactivated protein kinase; intracellular hormone receptor trafficking ACTIONS OF THYROID HORMONE [L-thyroxine (T 4 ); 3,5,3Ј-triiodo-L-thyronine (T 3 )] that are independent of ligand binding to nuclear thyroid hormone receptors are called nongenomic actions. Nongenomic effects of thyroid hormone are initiated outside the cell nucleus but may culminate in complex cellular events that are nucleus mediated (7, 8, 26 -29). Initiation of nongenomic actions includes a plasma membrane receptor for T 4 and T 3 on integrin ␣ v ␤ 3 that is linked to mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK) 1/2] for transduction of the hormone signal (3) and nuclear receptors residing in the cytosol of unstimulated cells, such as thyroid hormone receptor (TR) ␤1 (28).The phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (Akt) pathway is an important regulator of cellular growth, metabolism, and survival (13, 19). Studies of Storey et al. (38) indi...

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Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated

Cited by 114 publications

References 22 publications

Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac)

Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac)

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

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