The Tyrosine Kinase Inhibitor STI571 Induces Cellular Clearance of PrPSc in Prion-infected Cells

Ertmer, Alexa; Gilch, Sabine; Yun, Seong‐Wook; Flechsig, Eckhard; Klebl, Bert; Stein-Gerlach, Matthias; Klein, Michael A.; Schätzl, Hermann

doi:10.1074/jbc.m405652200

Cited by 119 publications

(122 citation statements)

References 57 publications

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“…In line with this, we previously published that imatinib can induce the cellular clearance of prion-infected cells from PrP Sc , the pathological isoform of the cellular prion protein (PrP c ), by activating its lysosomal degradation. 11 Here, we show that treatment with imatinib leads to a dose-dependent activation of cellular autophagy in immortalized as well as primary cells. These results possibly identify an additional mechanism by which imatinib induces growth arrest and promotes apoptosis in tumour cells.…”

Section: Introductionmentioning

confidence: 68%

“…11 To examine a direct effect of imatinib on cellular lysosomes, we analysed the lysosomal morphology under imatinib treatment. Lysosomes of treated and mock-treated cells were labelled with an antibody against the lysosomal membrane protein lamp-1 and analysed by indirect immunofluorescence and confocal microscopy.…”

Section: Imatinib Affects Lysosomal Morphology In Neuronal and Non-nementioning

confidence: 99%

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The anticancer drug imatinib induces cellular autophagy

et al. 2007

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The tyrosine kinase inhibitor imatinib (Gleevec, Novartis Pharmaceuticals Corporation; Basel, Switzerland) is a powerful drug for treatment of chronic myelogenous leukemia (CML) and other malignancies. It selectively targets various tyrosine kinases, thereby leading to growth arrest of respective cancer cells. Given its wide application, it is of high importance to know all related underlying molecular mechanisms. We had previously found that imatinib increases the cellular clearance of intracellular protein aggregates by targeting the abl pathway and thereby upregulating lysosomal activity. Here, we describe that imatinib dose dependently activates the cellular autophagy machinery in mammalian cells, independently of tissue type, species origin or immortalization status of cells. Autophagy is an archetypical cellular degradation mechanism implicated in many physiological and pathophysiological conditions. Our data link for the first time the process of autophagy with the mode of action of imatinib. Induction of autophagy might represent an additional mechanism of imatinib to induce growth arrest, promote apoptosis in cancer cells and eventually even promote tumour regression. Leukemia (2007) 21, 936-942.

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Section: Introductionmentioning

confidence: 68%

Section: Imatinib Affects Lysosomal Morphology In Neuronal and Non-nementioning

confidence: 99%

The anticancer drug imatinib induces cellular autophagy

et al. 2007

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“…One possibility is that imatinib may enhance the degradation rate of ABCG2 mRNA through activation of a pathway associated with lysosomal degradation. 16,17 This and other possible mechanisms are currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

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“…This suggests that also other Src-independent tyrosine kinase activities are upregulated in ScN2a cells. Of note, the tyrosine kinase inhibitor STI571 induces cellular clearance of PrP Sc in prion-infected cells by activation of lysosomal degradation of PrP Sc [30]. Thus, a possible scenario is that PrP Sc induces an increased tyrosine kinase activity, which slow down cellular clearance of PrP Sc and thereby facilitates PrP Sc replication.…”

Section: Discussionmentioning

confidence: 99%

Increased Src kinase level results in increased protein tyrosine phosphorylation in scrapie‐infected neuronal cell lines

et al. 2006

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We have studied how prion infection may affect the Src kinase activity in three different neuronal cell lines, ScGT1 and ScN2a, where ScGT1 were generated in our laboratory. By immunoblotting, using clone 28 -a monoclonal antibody recognizing active Src, we have found a 32 ± 6.3% and 75 ± 7.7% elevation in Src activity in ScGT1 and ScN2a cells, respectively, compared to uninfected cells. Immunocomplex in vitro kinase assay confirmed the increased Src activity. The increased Src kinase activity in scrapie-infected cells was further shown to correlate to an increased level of Src protein.In addition, an important increase in the protein tyrosine phosphorylation signal was observed in ScGT1 and ScN2a cells, which was further shown to be Src-dependent, as treatment with PP2 -a Src family kinase specific inhibitor, reversed the protein tyrosine phosphorylation profile. Abnormal Src-kinase activation and subsequent protein tyrosine phosphorylation may be key elements in the neuropathology of the prion diseases.

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The Tyrosine Kinase Inhibitor STI571 Induces Cellular Clearance of PrPSc in Prion-infected Cells

Cited by 119 publications

References 57 publications

The anticancer drug imatinib induces cellular autophagy

The anticancer drug imatinib induces cellular autophagy

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Increased Src kinase level results in increased protein tyrosine phosphorylation in scrapie‐infected neuronal cell lines

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