Ribosomal p70S6K basal activity increases upon induction of differentiation of myelomonocytic leukemic cell lines HL60, AML14 and MPD

Gómez‐Cambronero, Julian; Frye, T. D.; Baumann, Michael A.

doi:10.1016/j.leukres.2003.11.012

Cited by 9 publications

(5 citation statements)

References 42 publications

(41 reference statements)

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“…The data presented in Figure 8A show that MTLn3 ( 41 ) (rat breast cancer cells) demonstrate elevated cell invasion particularly with the overexpression of PLD2, Grb2 and WASP. Two other cancer cell lines, AML14-eosinophils (AML-14-Eo)( 45 ) and HL-60 neutrophilic (HL60-neut), both leukemic, also displayed similar patterns. Thus, the mechanistic findings could be extrapolated to other cell lines.…”

Section: Resultsmentioning

confidence: 81%

Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model

et al. 2013

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Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based shRNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, p<0.05) and their onset delayed when compared to control tumors. Second, we stably overexpressed PLD2 in low-invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (FIPI and NOPT). These inhibitors led to significant (>70%, p<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid (PA), WASp, Grb2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows that PLD has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target.

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Section: Resultsmentioning

confidence: 81%

Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model

et al. 2013

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“…The promyelocytic HL60 cells were grown in RPMI-1640 (PAA) supplemented with L-glutamine (2 mM) and 10% fetal bovine serum (FBS) at 37°C with 5% CO 2 . Cell differentiation was triggered by addition of DMSO (1.75%) for 4 days (dHL60 cells) 40. To check the differentiation from undifferentiated (uHL60) to differentiated neutrophil-like (dHL60) cells: To check the differentiation from undifferentiated (uHL60) to differentiated neutrophil-like (dHL60) cells, CD11b surface expression was checked by flow cytometry with a CD11b-FITC antibody (1:30).…”

Section: Methodsmentioning

confidence: 99%

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils

et al. 2011

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The directional migration of neutrophils towards inflammatory mediators, such as chemokines and cannabinoids, occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process. A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB 2 receptor (CB 2 R), but additional modulatory sites distinct from CB 2 R have recently been suggested to impact CB 2 R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB 2 R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB 2 R agonist 2-arachidonoylglycerol (2-AG), while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production. Using HEK293 and HL60 cell lines, along with primary neutrophils, we show that GPR55 and CB 2 R interfere with each other's signaling pathways at the level of small GTPases, such as Rac2 and Cdc42. This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils. Therefore, GPR55 limits the tissueinjuring inflammatory responses mediated by CB 2 R, while it synergizes with CB 2 R in recruiting neutrophils to sites of inflammation.

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“…Ingenuity pathway analysis (IPA) demonstrated that canonical pathways involved in eukaryotic initiation factor 2 (EIF2) as well as in eEIF4 and p70S6K signaling were enriched in TANs from β-glucan-trained mice ( Figure 2 C). Whereas the p70S6K signaling pathway has been linked to granulocytic differentiation and neutrophil functions, such as chemotaxis ( Gomez-Cambronero et al., 2004 ; Gomez-Cambronero et al., 2003 ), the EIF2 signaling pathway has been associated with reactive oxygen species (ROS)-induced stress ( Liu et al., 2008 ; Zeeshan et al., 2016 ; Zhang and Kaufman, 2008 ). Given that neutrophil ROS are linked to the anti-tumor effects of neutrophils ( Granot et al., 2011 ; Yan et al., 2014 ), we focused next on the ROS pathway in TANs from β-glucan-trained mice compared with that in TANs from control-treated mice.…”

Section: Resultsmentioning

confidence: 99%

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Kalafati

Kourtzelis

Schulte-Schrepping

et al. 2020

Cell

376

323

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Summary Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.

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Ribosomal p70S6K basal activity increases upon induction of differentiation of myelomonocytic leukemic cell lines HL60, AML14 and MPD

Cited by 9 publications

References 42 publications

Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model

Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

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