Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

Fischer, Bruno; Frei, Claudia; Moura, Ubiratan; Stahel, Rolf A.; Felley‐Bosco, Emanuela

doi:10.1016/j.lungcan.2012.07.005

Cited by 27 publications

(24 citation statements)

References 34 publications

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“…Quantitative abundance of the different transcripts varied depending on the cell line (Additional file 4: Figure S2B, C and D). To investigate whether GAS5 expression in MPM cells could be modulated by drugs inducing growth arrest, we treated MPM cells with either HhAntag or with NVP-BEZ235 as previously described [25,26]. ZL55SPT and SDM103T2 cells, grown in serum-free medium and at 3% of oxygen conditions, which allow maintenance of dedifferentiation properties [25], where treated during 48 h with HhAntag.…”

Section: Resultsmentioning

confidence: 99%

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GAS5 long non-coding RNA in malignant pleural mesothelioma

et al. 2014

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BackgroundMalignant pleural mesothelioma (MPM) is an aggressive cancer with short overall survival. Long non-coding RNAs (lncRNA) are a class of RNAs more than 200 nucleotides long that do not code for protein and are part of the 90% of the human genome that is transcribed. Earlier experimental studies in mice showed GAS5 (growth arrest specific transcript 5) gene deletion in asbestos driven mesothelioma. GAS5 encodes for a lncRNA whose function is not well known, but it has been shown to act as glucocorticoid receptor decoy and microRNA “sponge”. Our aim was to investigate the possible role of the GAS5 in the growth of MPM.MethodsPrimary MPM cultures grown in serum-free condition in 3% oxygen or MPM cell lines grown in serum-containing medium were used to investigate the modulation of GAS5 by growth arrest after inhibition of Hedgehog or PI3K/mTOR signalling. Cell cycle length was determined by EdU incorporation assay in doxycycline inducible short hairpinGAS5 clones generated from ZL55SPT cells. Gene expression was quantified by quantitative PCR. To investigate the GAS5 promoter, a 0.77 kb sequence was inserted into a pGL3 reporter vector and luciferase activity was determined after transfection into MPM cells. Localization of GAS5 lncRNA was identified by in situ hybridization. To characterize cells expressing GAS5, expression of podoplanin and Ki-67 was assessed by immunohistochemistry.ResultsGAS5 expression was lower in MPM cell lines compared to normal mesothelial cells. GAS5 was upregulated upon growth arrest induced by inhibition of Hedgehog and PI3K/mTOR signalling in in vitro MPM models. The increase in GAS5 lncRNA was accompanied by increased promoter activity. Silencing of GAS5 increased the expression of glucocorticoid responsive genes glucocorticoid inducible leucine-zipper and serum/glucocorticoid-regulated kinase-1 and shortened the length of the cell cycle. Drug induced growth arrest was associated with GAS5 accumulation in the nuclei. GAS5 was abundant in tumoral quiescent cells and it was correlated to podoplanin expression.ConclusionsThe observations that GAS5 levels modify cell proliferation in vitro, and that GAS5 expression in MPM tissue is associated with cell quiescence and podoplanin expression support a role of GAS5 in MPM biology.

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Section: Resultsmentioning

confidence: 99%

“…NP3 cells were also grown in serum-free medium. To induce growth arrest, cells were treated either with Hedgehog signaling inhibitor (HhAntag) [25] or with dual PI3K/mTOR inhibitor (NVP-BEZ235, Novartis, Switzerland) [26], as previously described.…”

Section: Methodsmentioning

confidence: 99%

GAS5 long non-coding RNA in malignant pleural mesothelioma

et al. 2014

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“…Several possible etiological mechanisms have been delineated so far, which include elevated expression of ATP binding cassette (ABC) transporters such as MDR1 [19] and ABCG2 [20], high expression of aldehyde dehydrogenase [21], expression of antiapoptotic proteins such as survivin [22]. Since the discovery of AKT as a target of phosphoinositide 3-kinase almost two decades ago and the subsequent evidence indicating the increased cell survival upon the upregulation of AKT, there has been large interests to inhibit this pathway to treat cancer [23].…”

Section: Introductionmentioning

confidence: 99%

Chemoresistance of CD133 + colon cancer may be related with increased survivin expression

Lee

Mia-Jan

et al. 2015

Biochemical and Biophysical Research Communications

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“…However, the observed activation of multiple RTKs in mesothelioma suggests that transforming activity is dependent on coordinated activity of multiple tyrosine kinases (Kawaguchi et al , 2009; Menges et al , 2010; Perrone et al , 2010; Brevet et al , 2011; Ou et al , 2011b), and simultaneous inhibition of multiple kinases by cocktails of small-molecule kinase inhibitors or single-agent HSP90 inhibitors elicits compelling pro-apoptotic and anti-proliferative responses in mesothelioma preclinical models (Okamoto et al , 2008; Kawaguchi et al , 2009; Ou et al , 2011b). In addition to the evidence for PI3K/AKT and RAF/MEK/MAPK activation in mesothelioma initiation, there is likewise substantial evidence that these key signalling pathways are crucial in maintaining the transformed state, and in mesothelioma metastasis (Altomare et al , 2005; Cole et al , 2006; Patel et al , 2007; Jacobson et al , 2009; Suzuki et al , 2009; Shukla et al , 2011; Carbone and Yang, 2012; Cedres et al , 2012; Fischer et al , 2012; Menges et al , 2012; Miyoshi et al , 2012; Pinton et al , 2012). In this study, we demonstrate PI3K/AKT/mTOR dependency on multiple activated RTKs in mesothelioma.…”

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Multipoint targeting of the PI3K/mTOR pathway in mesothelioma

Zhou

Liu

et al. 2014

Br J Cancer

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Background:Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.Methods:Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.Results:We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.Conclusions:These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.

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Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

Cited by 27 publications

References 34 publications

GAS5 long non-coding RNA in malignant pleural mesothelioma

GAS5 long non-coding RNA in malignant pleural mesothelioma

Chemoresistance of CD133 + colon cancer may be related with increased survivin expression

Multipoint targeting of the PI3K/mTOR pathway in mesothelioma

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