Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation
Abstract Background Depletion of tryptophan and the accumulation of tryptophan metabolites mediated by the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer cells in the same microenvironment appear not to be affected. Mechanism...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-018-0301-7 |
| _version_ | 1819052426336927744 |
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| author | Petr Tomek Shanti K. Gore Chloe L. Potts Cristin G. Print Michael A. Black Ariane Hallermayr Michael Kilian Evelyn Sattlegger Lai-Ming Ching |
| author_facet | Petr Tomek Shanti K. Gore Chloe L. Potts Cristin G. Print Michael A. Black Ariane Hallermayr Michael Kilian Evelyn Sattlegger Lai-Ming Ching |
| author_sort | Petr Tomek |
| collection | DOAJ |
| description | Abstract Background Depletion of tryptophan and the accumulation of tryptophan metabolites mediated by the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer cells in the same microenvironment appear not to be affected. Mechanisms whereby cancer cells resist accelerated tryptophan degradation are not completely understood. We hypothesize that cancer cells co-opt IMPACT (the product of IMPrinted and AnCienT gene), to withstand periods of tryptophan deficiency. Methods A range of bioinformatic techniques including correlation and gene set variation analyses was applied to genomic datasets of cancer (The Cancer Genome Atlas) and normal (Genotype Tissue Expression Project) tissues to investigate IMPACT’s role in cancer. Survival of IMPACT-overexpressing GL261 glioma cells and their wild type counterparts cultured in low tryptophan media was assessed using fluorescence microscopy and MTT bio-reduction assay. Expression of the Integrated Stress Response proteins was measured using Western blotting. Results We found IMPACT to be upregulated and frequently amplified in a broad range of clinical cancers relative to their non-malignant tissue counterparts. In a subset of clinical cancers, high IMPACT expression associated with decreased activity of pathways and genes involved in stress response and with increased activity of translational regulation such as the mTOR pathway. Experimental studies using the GL261 glioma line showed that cells engineered to overexpress IMPACT, gained a survival advantage over wild-type lines when cultured under limiting tryptophan concentrations. No significant difference in the expression of proteins in the Integrated Stress Response pathway was detected in tryptophan-deprived GL261 IMPACT-overexpressors compared to that in wild-type cells. IMPACT-overexpressing GL261 cells but not their wild-type counterparts, showed marked enlargement of their nuclei and cytoplasmic area when stressed by tryptophan deprivation. Conclusions The bioinformatics data together with our laboratory studies, support the hypothesis that IMPACT mediates a protective mechanism allowing cancer cells to overcome microenvironmental stresses such as tryptophan deficiency. |
| first_indexed | 2024-12-21T12:19:39Z |
| format | Article |
| id | doaj.art-ba904e871d9947f4afac06258adc6a56 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-21T12:19:39Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-ba904e871d9947f4afac06258adc6a562022-12-21T19:04:21ZengBMCCell Communication and Signaling1478-811X2018-11-0116111510.1186/s12964-018-0301-7Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivationPetr Tomek0Shanti K. Gore1Chloe L. Potts2Cristin G. Print3Michael A. Black4Ariane Hallermayr5Michael Kilian6Evelyn Sattlegger7Lai-Ming Ching8Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandDepartment of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of AucklandDepartment of Biochemistry, University of OtagoAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandInstitute of Natural and Mathematical Sciences, Massey UniversityAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of AucklandAbstract Background Depletion of tryptophan and the accumulation of tryptophan metabolites mediated by the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer cells in the same microenvironment appear not to be affected. Mechanisms whereby cancer cells resist accelerated tryptophan degradation are not completely understood. We hypothesize that cancer cells co-opt IMPACT (the product of IMPrinted and AnCienT gene), to withstand periods of tryptophan deficiency. Methods A range of bioinformatic techniques including correlation and gene set variation analyses was applied to genomic datasets of cancer (The Cancer Genome Atlas) and normal (Genotype Tissue Expression Project) tissues to investigate IMPACT’s role in cancer. Survival of IMPACT-overexpressing GL261 glioma cells and their wild type counterparts cultured in low tryptophan media was assessed using fluorescence microscopy and MTT bio-reduction assay. Expression of the Integrated Stress Response proteins was measured using Western blotting. Results We found IMPACT to be upregulated and frequently amplified in a broad range of clinical cancers relative to their non-malignant tissue counterparts. In a subset of clinical cancers, high IMPACT expression associated with decreased activity of pathways and genes involved in stress response and with increased activity of translational regulation such as the mTOR pathway. Experimental studies using the GL261 glioma line showed that cells engineered to overexpress IMPACT, gained a survival advantage over wild-type lines when cultured under limiting tryptophan concentrations. No significant difference in the expression of proteins in the Integrated Stress Response pathway was detected in tryptophan-deprived GL261 IMPACT-overexpressors compared to that in wild-type cells. IMPACT-overexpressing GL261 cells but not their wild-type counterparts, showed marked enlargement of their nuclei and cytoplasmic area when stressed by tryptophan deprivation. Conclusions The bioinformatics data together with our laboratory studies, support the hypothesis that IMPACT mediates a protective mechanism allowing cancer cells to overcome microenvironmental stresses such as tryptophan deficiency.http://link.springer.com/article/10.1186/s12964-018-0301-7IMPACTIDO1Immune suppressionCancer cell survival |
| spellingShingle | Petr Tomek Shanti K. Gore Chloe L. Potts Cristin G. Print Michael A. Black Ariane Hallermayr Michael Kilian Evelyn Sattlegger Lai-Ming Ching Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation Cell Communication and Signaling IMPACT IDO1 Immune suppression Cancer cell survival |
| title | Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation |
| title_full | Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation |
| title_fullStr | Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation |
| title_full_unstemmed | Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation |
| title_short | Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation |
| title_sort | imprinted and ancient gene a potential mediator of cancer cell survival during tryptophan deprivation |
| topic | IMPACT IDO1 Immune suppression Cancer cell survival |
| url | http://link.springer.com/article/10.1186/s12964-018-0301-7 |
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