Interleukin‐3 is an autocrine growth factor of human megakaryoblasts, the DAMI and MEG‐01 cells

Chen, Yuan Zhong; Gu, Xue; Caen, Jacques P.; Han, Zhong Chao

doi:10.1111/j.1365-2141.1994.tb05063.x

Cited by 15 publications

(4 citation statements)

References 28 publications

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“…A number of previous in vitro studies have demonstrated that a substantial proportion of fresh leukemic blasts or leukemic cell lines may produce hematopoietic growth factors, bear receptors for the produced factors, and be growth inhibited by neutralization of the produced factors [13][14][15][16][17][18][19]. Our studies extend these observations by demonstrating that AML14.3D10 cells use endogenously produced GM-CSF to activate intracellular GM-CSFrelated signal transduction pathways.…”

Section: Discussionsupporting

confidence: 78%

Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells

et al. 1997

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The AML14.3D10 human myeloid leukemic cell line expresses receptors for granulocytemacrophage colony stimulating factor (GM-CSF) and interleukin-5 (IL-5), but not IL-3. We have found that this cell line produces GM-CSF in amounts up to 113 pg/ml in culture supernatants. Deprivation of endogenous GM-CSF by addition of neutralizing anti-GM-CSF antibody strongly inhibits proliferation of the cells, suggesting a GM-CSF autocrine growth mechanism. To examine whether endogenously produced GM-CSF activates intracellular GM-CSF/IL-3/IL-5-related signal transduction pathways, we performed antiphosphotyrosine immunoblotting of cell lysates of AML14.3D10 cells before and after deprivation of endogenous GM-CSF. We found constitutive tyrosine-phosphorylation of a number of proteins in AML14.3D10 that could not be detectably increased by the addition of exogenous GM-CSF, IL-3, or IL-5. However, GM-CSF-deprived cells demonstrated a marked increase in phosphorylation of proteins of identical molecular mass following addition of GM-CSF and IL-5, but not IL-3, consistent with the receptor expression of the cells and the known use of the same signaling pathways by the three cytokines. This suggests that AML14.3D10 cells use endogenously produced GM-CSF to activate signal transduction pathways, interfering with activation by exogenous cytokine until the endogenous stimulation is removed. We then assessed the activation of the ␤-subunit common to the GM-CSF/IL-3/IL-5 receptors (␤c), JAK2 and p53/56 lyn, known to be involved in the common signaling pathways of the three cytokines. We found that phosphorylation of ␤c and JAK2 in response to GM-CSF and IL-5 could be markedly enhanced by depriving cells of endogenous GM-CSF. Constitutive hyperphosphorylation of lyn was found in AML14.3D10 cells, and no further activation of lyn in response to cytokine was demonstrable in GM-CSF-deprived cells, suggesting that lyn is activated in this cell line by a mechanism other than GM-CSF. These studies represent the first demonstration of autocrine activation of intracellular cytokine signaling pathways by malignant hematopoietic cells. Because the addition of anti-GM-CSF to cell cultures improved responsiveness of intracellular signal transducing molecules to exogenous GM-CSF and IL-5, it can be inferred that endogenously produced GM-CSF exerts its effects by secretion and binding to surface GM-CSF receptors, although an intracellular component to signaling cannot be excluded. These observations provide further information regarding an autocrine contribution to leukemic cell growth, and establish a new model for study of these events. Am. J. Hematol. 56:79-85, 1997.

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Section: Discussionsupporting

confidence: 78%

Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells

et al. 1997

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“…On the other hand, List and colleges recently showed that inhibition by PSC 833 of the ABC1 transporter interrupts the efflux of IL-1β form leukemia cells and causes apoptosis which is avoided by exogenous substitution of IL-1β [171]. It is also known that both IL-3 and IL-6 may act as endogenous growth factors in autonomously growing leukemic cell lines [177,178], and endogenously produced GM-CSF may promote growth of malignant hematopoietic cells by secretion and binding to surface GM-CSF receptors [179]. Therefore, there are several candidates for a growth regulatory molecule working in an autocrine loop maintained by Pgp, but at present no study has provided proof of such a mechanism or identified the effector molecule.…”

Section: Inhibition Of P-glycoprotein May Trigger Apoptosismentioning

confidence: 99%

P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer

Lehne¹

2000

CDT

147

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Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One important mechanism of MDR involves the multidrug transporter, P-glycoprotein (Pgp), which confers upon cancer cells the ability to resist lethal doses of certain cytotoxic drugs by pumping the drugs out of the cells and thus reducing their cytotoxicity. Pgp belongs to the ATP-binding cassette (ABC) family of transporter molecules which require hydrolysis of ATP to run the transport mechanism. The substrates of Pgp may be endogenous (steroid hormones, cytokines) or exogenous (cytostatic drugs). A number of studies have demonstrated a negative correlation between Pgp expression levels and chemosensitivity or survival in a range of human malignancies. In principle, Pgp mediated drug resistance can be circumvented by treatment regimens that either exclude Pgp substrate drugs or include Pgp inhibitory agents. Experimental studies have demonstrated that certain structural modifications of anthracyclines confer the ability to escape Pgp transport. The therapeutic benefit of Pgp inhibitors as chemosensitizers is currently being explored in phase III clinical trials, and the first promising results have already been reported. Another therapeutic option for Pgp inhibitors has recently evolved as several Pgp inhibitors, many of which are generally low-toxic substances, by themselves constrain proliferation and cause cell death by apoptosis in certain MDR cancer cell lines. The dual effect of Pgp inhibitors, targeting MDR cancer cells selectively, may translate into improved efficacy of cancer chemotherapy and perhaps new and less toxic drug treatment strategies in human MDR cancer.

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“…On the other hand, List and colleagues 37 have demonstrated that inhibition by PSC 833 of the ABC1 transporter interrupts the efflux of IL-1␤ from cultured leukemia cells and causes apoptosis, which is avoided by exogenous substitution of IL-1␤. It is also known that both IL-3 and IL-6 may act as endogenous growth factors in autonomously growing leukemic cell lines, 45,46 and endogenously produced GM-CSF may promote growth of malignant hematopoietic cells by secretion and binding to surface GM-CSF receptors. 47 Therefore, there are several candidates for a growth regulatory molecule working in an autocrine loop maintained by Pgp, but at present no study has provided proof of such a mechanism or identified the effector molecule.…”

Section: Figurementioning

confidence: 99%

The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice

et al. 2002

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Circumvention of chemoresistance in cancer may involve several modulator drugs with high affinity for the multidrug transporter P-glycoprotein (Pgp), which is expressed in a number of multi-resistant malignancies. Pgp acts as a membrane efflux pump with broad substrate specificity including antineoplastic drugs and endogenous substances such as certain cytokines and sphingolipids. Therefore, the consequence of Pgp blockade could be far more complex than intracellular drug retention. In the present study exposure of the Pgp inhibitor, PSC 833 (1200 ng/ml), to Pgp expressing KG1a/200 human leukemia cells provoked cell cycle arrest and apoptosis in vitro. This finding was put to test in vivo using a xenotransplant model of KG1a/200 human cells intravenously inoculated into non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. The animals were randomly allocated to receive treatment with PSC 833 (n = 32) or placebo (n = 24). PSC 833 (30 mg/kg) was subcutaneously injected six or 12 times separated by 48-96 h. The overall mean whole blood concentration of PSC 833 was 1191 ± 60 ng/ml (s.e.m.) at 20 h after administration. Tumor engraftment was significantly reduced in the treatment group (P = 0.037), which also had prolonged survival compared to control animals (P = 0.0016). This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data raise the possibility of alternative exploitation of modulators in cancer chemotherapy.

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Interleukin‐3 is an autocrine growth factor of human megakaryoblasts, the DAMI and MEG‐01 cells

Cited by 15 publications

References 28 publications

Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells

Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells

P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer

The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice

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