Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment

Subramanian, Manikandan; Shaha, Chandrima

doi:10.4049/jimmunol.179.4.2330

Cited by 59 publications

(55 citation statements)

References 57 publications

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“…Although the Fas-mediated apoptosis after c-FLIP siRNA inhibition in B16 cells showed no difference compared with control siRNA, we cannot exclude that c-FLIP plays a role in the Fas resistance of B16 cells, because the effect of c-FLIP knock down is mild, and the expression of c-FLIP decreases only ∼50%. It was reported that activation of the ERK pathway and subsequent induction of antiapoptotic proteins, such as Bcl-2, play important roles in the survival of CD8 + T and NK cells (44,45) In B16 tumor cells stimulated by FasL + EXO, we found that Bcl-2 was upregulated after EXO stimulation, and specific inhibitors of ERK and NF-kB activation could decrease the expression of Bcl-2. But there was no increasing apoptosis in the B16 cells treated with Bcl-2 inhibitor compared with the group treated with DMSO or control, which suggests that Bcl-2 may not be involved in the Fas resistance of B16 tumor cells induced by FasL-expressed EXO (data not shown).…”

Section: Discussionmentioning

confidence: 64%

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Cai

Yang

et al. 2012

The Journal of Immunology

233

174

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Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8+ T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape.

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Section: Discussionmentioning

confidence: 64%

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Cai

Yang

et al. 2012

The Journal of Immunology

233

174

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“…The homogenate was centrifuged at 1,300 Â g to isolate the nuclear fraction followed by centrifugation at 17,000 Â g in Optima XL-100K (Beckman Coulter) to isolate the mitochondrial fraction. Postmitochondrial supernatant centrifuged at 100,000 Â g provided the cytosolic fraction (23).…”

Section: Subcellular Fractionationmentioning

confidence: 99%

Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

Tripathi

Samadder

Gupta

et al. 2011

Molecular Cancer Therapeutics

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Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy, and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7, respectively, whereas combination treatment activated all 4 caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by short hairpin RNA during drug treatment decreased p21 levels but caused survivin increase, thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells. Mol Cancer Ther; 10(2); 255-68. Ó2011 AACR.

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“…N-TER TM Nanoparticle siRNA Transfection System (SigmaAldrich, N2913) was used to transfect both macrophage-like THP-1 cells and HsMDMs as reported earlier. 52 …”

Section: Mirna Transfectionmentioning

confidence: 99%

“…Images were captured at 63x magnification using a Leica TCS SP5 II (Leica Microsystems, Wetzlar, Germany) confocal microscope and were processed for algorithmic quantification of LC3-II puncta using custom-written ImageJ macro-containing plug-ins as described previously. 52 At least 100 cells per condition were counted.…”

Section: Confocal Microscopymentioning

confidence: 99%

MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

et al. 2016

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Leishmania is an obligate intracellular parasite that replicates inside phagolysosomes or parasitophorous vacuoles (PV) of the monocyte/macrophage lineage. It reprograms macrophages and produces a metabolic state conducive to successful infection and multiplication. MicroRNAs (miRNAs), a class of small 22 to 24 nucleotide noncoding regulatory RNAs alter the gene expression and consequently proteome output by targeting mRNAs, may play a regulatory role in modulating host cell functions. In the present study, we demonstrate the novel regulatory role of host microRNA, MIR30A-3p in modulation of host cell macroautophagy/autophagy after infection with L. donovani. Our in vitro studies showed that MIR30A-3p expression was significantly enhanced after L. donovani infection in a time-dependent manner. Transient transfection with a MIR30A-3p inhibitor followed by L. donovani infection promoted the autophagic response and decreased the intracellular parasite burden in both THP-1 cells and human monocytederived macrophages (HsMDM). BECN1/Beclin 1, the mammalian ortholog of yeast Vps30/Atg6, is a key autophagy-promoting protein that plays a key role in the regulation of cell death and survival. We report BECN1-dependent modulation of host cell autophagy in response to L. donovani infection. Pretreatment of L. donovani-infected macrophages with the MIR30A-3p mimic decreased and with antagomir increased the expression of BECN1 protein. We demonstrate that BECN1 is a potential target of MIR30A-3p and this miRNA negatively regulates BECN1 expression. Our present study reveals for the first time a novel role of MIR30A-3p in regulating autophagy-mediated L. donovani elimination by targeting BECN1. The present study has significant impact for the treatment of visceral leishmaniasis.

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Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment

Cited by 59 publications

References 57 publications

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

MicroRNA expression profiling ofLeishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy

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