Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

Kovacic, Jason C.; Gupta, Rohit; Lee, Angela C; Ma, Mingchao; Fang, Fang; Tolbert, Claire N.; Walts, Avram D.; Beltran, Leilani E.; San, Hong; Chen, Guibin; Hilaire, Cynthia St.; Boehm, Manfred

doi:10.1172/jci40364

Cited by 84 publications

(100 citation statements)

References 68 publications

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“…Our data also indicated that STAT3 contributed to RANTES overexpression in TRM-7 cells. Inhibition of STAT3 phosphorylation led to downregulation of RANTES mRNA levels (40). This was supported by the observation that STAT3 regulated RANTES promoter activity in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 67%

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STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Lee

et al. 2013

Molecular Cancer Research

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The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates antiapoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of antiapoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31-42. Ó2012 AACR. IntroductionBreast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds that of all other cancers, and its incidence is increasing (1). In women younger than 50 years with breast cancer, chemotherapy increases the 15-year survival rate by 10%,

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Section: Discussionmentioning

confidence: 67%

“…Phosphorylated STAT3 upregulates RANTES expression RANTES is a STAT3 target gene (40,41). To investigate the role of STAT3 activation in RANTES expression, we used the JAK2 inhibitor, AG490, which suppresses constitutive STAT3 activation.…”

Section: Rantes-mediated Stat3 Activationmentioning

confidence: 99%

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Lee

et al. 2013

Molecular Cancer Research

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“…Open Biosystems TC1 library numbers TCRN0000071453 to TCRN0000071457 were used (pLKO.1 vector). 33 Control shRNA virus SHC-002 (SigmaAldrich) was used to create a stable control knockdown line. Cells were maintained in selection media containing 2 g/mL puromycin, to which the lentiviral vectors conferred resistance but completely killed uninfected cells.…”

Section: Shrna Knockdownmentioning

confidence: 99%

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Goldsmith

Uronis

Jobin

2011

The American Journal of Pathology

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Opiates have long been used as analgesics to relieve pain associated with various medical conditions. Here, we evaluated the effect and mechanism of mu opioid signaling on the intestinal wound healing response and assessed downstream pathways known to be protective against intestinal injury. Mice (C57BL/6) were exposed to 3% dextran sodium sulfate (DSS) for 7 days or 4% DSS for 5 days followed by 7 days of water. The mu opioid receptor (MOR)-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA) and the antagonist cyprodime were injected s.c. daily for in vivo studies or used for in vitro analysis. We found that MOR activation attenuated DSS-induced histologic and gross intestinal injury and weight loss; diminished Ifng, Tnf, and Il6 mRNA expression; and promoted intestinal healing during recovery. DALDA also enhanced colonocyte proliferation (Ki-67 staining) by 350%. MOR activation increased Stat3 phosphorylation in both DALDA-treated mice and the CMT-93 cell line. Importantly, DALDAinduced colonocyte migration was completely ablated by shStat3 knockdown. Together, this work shows that MOR activation protects against and enhances recovery from DSS-induced intestinal injury. This is associated with an increase in Stat3 activation. Furthermore, Stat3 is required for DALDA-induced colonocyte migration. Consequently, manipulation of MOR signaling may represent a novel means to promote mucosal healing and to maintain intestinal homeostasis after intestinal injury.

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“…RANTES induces the chemotaxis of multiple immune cells (17) and is secreted by many cell types including fibroblasts (18), epithelial cells (19), and vascular smooth muscle cells (20). High levels of RANTES are associated with several pathologies including atherosclerosis (21), various cancers (22,23), diabetes (24), glomerulonephritis (25), and rheumatoid arthritis (26).…”

mentioning

confidence: 99%

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

Adada

Orr-Gandy

Snider

et al. 2013

Journal of Biological Chemistry

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Background: SK1 is widely involved in promoting inflammatory diseases. Results: Unexpectedly, loss of SK1 caused an increase in chemokines upon TNF stimulation. This occurred through regulation of p38 MAPK but independently of NF-B. Conclusion: SK1 negatively regulates RANTES expression through the p38 MAPK pathway. Significance: Targeting SK1 in therapy may affect inflammatory conditions by up-regulating chemokines independently of NF-B.

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Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

Cited by 84 publications

References 68 publications

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

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