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Behnam-Motlagh, Parviz
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Publications (10 of 20) Show all publications
Geoghegan, F., Buckland, R. J., Rogers, E. T., Khalifa, K., O'Connor, E. B., Rooney, M. F., . . . Porter, R. K. (2017). Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells. OncoTarget, 8(55), 94711-94725
Open this publication in new window or tab >>Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed) Published
Abstract [en]

Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
cisplatin resistance, bioenergetics, SIRT3, non-small cell lung cancer, mesothelioma
National Category
Cell Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142242 (URN)10.18632/oncotarget.21885 (DOI)000414608400121 ()
Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2018-06-09Bibliographically approved
Tyler, A., Johansson, A., Karlsson, T., Kumar Gudey, S., Brännström, T., Grankvist, K. & Behnam-Motlagh, P. (2015). Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells. Experimental Cell Research, 336(1), 23-32
Open this publication in new window or tab >>Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells
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2015 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 336, no 1, p. 23-32Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance.

METHODS: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analysed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72h on expression and cisplatin cytotoxicity was tested.

RESULTS: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells.

CONCLUSIONS: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells.

Keywords
Cisplatin,  Glucosylceramide synthase (GCS),  Globotriaosylceramide (Gb3),  Lung cancer,  Multidrug resistance 1/P-glycoprotein (MDR1), Multidrug resistance-associated protein 1 (MRP1),  Malignant pleural mesothelioma (MPM),  DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP),  Cyclosporin A,  Acquired drug resistance
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:umu:diva-103786 (URN)10.1016/j.yexcr.2015.05.012 (DOI)000358821700003 ()26004871 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2015-05-30 Created: 2015-05-30 Last updated: 2018-06-07Bibliographically approved
Lindqvist, B. M., Wingren, S., Motlagh, P. B. & Nilsson, T. K. (2014). Whole genome DNA methylation signature of HER2-positive breast cancer. Epigenetics, 9(8), 1149-1162
Open this publication in new window or tab >>Whole genome DNA methylation signature of HER2-positive breast cancer
2014 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1149-1162Article in journal (Refereed) Published
Abstract [en]

In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

Keywords
DNA methylation, HER2-positive breast cancer, Illumina Infinium HumanMethylation450 BeadChip
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-93833 (URN)10.4161/epi.29632 (DOI)000341360600010 ()25089541 (PubMedID)
Available from: 2014-10-08 Created: 2014-10-01 Last updated: 2018-06-07Bibliographically approved
Michels, J., Vitale, I., Galluzzi, L., Adam, J., Olaussen, K. A., Kepp, O., . . . Kroemer, G. (2013). Cisplatin Resistance Associated with PARP Hyperactivation. Cancer Research, 73(7), 2271-2280
Open this publication in new window or tab >>Cisplatin Resistance Associated with PARP Hyperactivation
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2013 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 7, p. 2271-2280Article in journal (Refereed) Published
Abstract [en]

Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80.

Place, publisher, year, edition, pages
Philadelphia: American Association for Cancer Research, 2013
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-70139 (URN)10.1158/0008-5472.CAN-12-3000 (DOI)000316995600024 ()
Available from: 2013-05-09 Created: 2013-05-06 Last updated: 2018-06-08Bibliographically approved
Behnam-Mothlag, P., Tyler, A., Brännström, T., Karlsson, T., Johansson, A. & Grankvist, K. (2012). Cisplatin Resistance in Malignant Pleural Mesothelioma. In: Alexander Zubritsky (Ed.), Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis (pp. 169-186). Zagreb: InTech, 11
Open this publication in new window or tab >>Cisplatin Resistance in Malignant Pleural Mesothelioma
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2012 (English)In: Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis / [ed] Alexander Zubritsky, Zagreb: InTech, 2012, Vol. 11, p. 169-186Chapter in book (Refereed)
Place, publisher, year, edition, pages
Zagreb: InTech, 2012
Keywords
Mesothelioma, drug resistance, bacterial toxins
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-54085 (URN)10.5772/31685 (DOI)978-953-307-845-8 (ISBN)
Available from: 2012-05-11 Created: 2012-04-15 Last updated: 2018-06-08Bibliographically approved
Galluzzi, L., Vitale, I., Senovilla, L., Olaussen, K. A., Pinna, G., Eisenberg, T., . . . Kroemer, G. (2012). Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer. CELL REPORTS, 2(2), 257-269
Open this publication in new window or tab >>Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer
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2012 (English)In: CELL REPORTS, ISSN 2211-1247, Vol. 2, no 2, p. 257-269Article in journal (Refereed) Published
Abstract [en]

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

Place, publisher, year, edition, pages
Cambridge: Cell press, 2012
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-61575 (URN)10.1016/j.celrep.2012.06.017 (DOI)000309715100007 ()
Available from: 2012-11-27 Created: 2012-11-20 Last updated: 2018-06-08Bibliographically approved
Behnam Motlagh, P., Tyler, A., Johansson, A., Brännstrom, T. & Grankvist, K. (2011). Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach. Paper presented at European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Stockholm, Sweden, September 23-27 2011. Oxford: Pergamon, 47
Open this publication in new window or tab >>Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach
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2011 (English)Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
Oxford: Pergamon, 2011
Series
European Journal of Cancer, ISSN 0959-8049 ; Vol. 47 Suppl. 1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-49260 (URN)10.1016/S0959-8049(11)72336-X (DOI)000295752802130 ()
Conference
European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Stockholm, Sweden, September 23-27 2011
Available from: 2011-11-09 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
Tyler, A., Jansson, V., Behnam Motlagh, P., Johansson, A. & Grankvist, K. (2011). Effect of BH3-mimetics GX15-070 and ABT-737 on cisplatin resistance in malignant pleural mesothelioma cells. Paper presented at European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Stockholm, Sweden, September 23-27 2011. Oxford: Pergamon, 47
Open this publication in new window or tab >>Effect of BH3-mimetics GX15-070 and ABT-737 on cisplatin resistance in malignant pleural mesothelioma cells
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2011 (English)Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
Oxford: Pergamon, 2011
Series
European Journal of Cancer ; Vol. 47 Suppl. 1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-49261 (URN)10.1016/S0959-8049(11)72336-X (DOI)000295752802131 ()
Conference
European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Stockholm, Sweden, September 23-27 2011
Available from: 2011-11-09 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
Johansson, D., Andersson, C., Moharer, J., Johansson, A. & Behnam-Motlagh, P. (2010). Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells. British Journal of Cancer, 102(2), 383-391
Open this publication in new window or tab >>Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells
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2010 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 102, no 2, p. 383-391Article in journal (Refereed) Published
Abstract [en]

Background:

A major problem with cisplatin treatment is the development of acquired-drug resistance of the tumour cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the membrane glycolipid globotriasosylceramide (Gb3), a molecule associated with drug resistance. Cisplatin- and VT-1-induced apoptosis involves mitogen-activated protein kinase (MAPK) activation, and deactivation of MAPKs is associated with cisplatin resistance. This study aimed to investigate whether a sub-toxic concentration of VT-1 could enhance cisplatin-induced apoptosis and overcome acquired-cisplatin resistance in cultured cancer cell lines.

Method:

P31 and H1299 cells with corresponding cisplatin-resistant sub-lines (P31res/H1299res) were incubated with VT-1 and/or cisplatin followed by determination of Gb3 expression, cell viability, apoptosis, and signalling pathways.

Results:

Cells from the resistant sub-lines had elevated Gb3 expression compared with the parental cell lines, and cisplatin further increased Gb3 expression, whereas VT-1 reduced the percentage of Gb3-expressing cells. Combination of cisplatin and sub-toxic concentrations of VT-1 led to a super-additive increase of cytotoxicity and TUNEL staining, especially in the cisplatin-resistant sub-lines. Blockade of Gb3 synthesis by a Gb3 synthesis inhibitor not only led to eradicated TUNEL staining of P31 cells, but also sensitised P31res cells to the induction of apoptosis by cisplatin alone. Cisplatin- and VT-1-induced apoptosis involved the MAPK pathways with increased C-Jun N-terminal kinase and MAPK kinase-3 and -6 phosphorylation.

Conclusions:

We show the presence of Gb3 in acquired-cisplatin resistance in P31res and H1299res cells. Cisplatin up-regulated Gb3 expression in all cells and thus sensitised the cells to VT-1-induced cytotoxicity. A strong super-additive effect of combined cisplatin and a sub-toxic concentration of VT-1 in cisplatin-resistant malignant pleural mesothelioma cells were observed, indicating a new potential clinical-treatment approach.

Place, publisher, year, edition, pages
Nature Publishing Group, 2010
Keywords
acquired resistance, apoptosis, cisplatin, Gb3, mesothelioma, verotoxin-1
Identifiers
urn:nbn:se:umu:diva-3155 (URN)10.1038/sj.bjc.6605467 (DOI)000273728500019 ()
Available from: 2008-05-05 Created: 2008-05-05 Last updated: 2018-06-09Bibliographically approved
Behnam-Motlagh, P., Tyler, A., Grankvist, K. & Johansson, A. (2010). Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy. Toxins, 2(10), 2467-2477
Open this publication in new window or tab >>Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy
2010 (English)In: Toxins, ISSN 2072-6651, Vol. 2, no 10, p. 2467-2477Article, review/survey (Refereed) Published
Abstract [en]

A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors.

Place, publisher, year, edition, pages
Basel: MDPI, 2010
Keywords
apoptosis, cancer, Gb3, verotoxin-1, multi-drug resistance, MDR1, P-gp
National Category
Cancer and Oncology
Research subject
cell research
Identifiers
urn:nbn:se:umu:diva-40654 (URN)10.3390/toxins2102467 (DOI)000208435600007 ()
Available from: 2011-03-07 Created: 2011-03-03 Last updated: 2018-06-08Bibliographically approved
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