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Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells.

ABSTRACT: Recently, a subpopulation of tumor cells, called cancer stem cells (CSC), has been characterized, and these have emerged as a major topic in cancer research. CSC are proposed to repair DNA damage more efficiently than the rest of tumor cells, resisting chemotherapy or radiotherapy and causing clinical recurrence and metastasis. We aimed to determine the molecular basis of radioresistance and first compared the response to ionizing radiation (IR) between cancer stem cell-enriched cultures grown as spheres and conventional tumor cell line cultures grown as monolayer, from HeLa and MCF-7 cancer cell lines. To verify that our sphere cultures were enriched in CSC, we evaluated the double staining of CD49f and ALDH activity for HeLa cells by flow cytometry. We then evaluated whether differences could exist in sensor elements in the DNA damage response pathway among these cultures. We found that CSC cultures showed less sensitivity to radiation than conventional tumor cell line cultures. We observed a higher baseline expression of activated response sensor proteins of DNA damage, such as ATM, H2A.X, and PARP1, in untreated CSC cultures. These findings provide the first evidence, to our knowledge, that DNA damage response sensor proteins are present and preferentially activated in CSC, as opposed to the bulk of cells in monolayer cultures. Likewise, they provide the basis for biological differences in response to IR between CSC and other tumor cell populations. Understanding the DNA damage response pathway may provide therapeutic targets to sensitize CSC to cytotoxic therapies to improve current cancer treatments.

SUBMITTER: Valencia-Gonzalez HA

PROVIDER: S-EPMC6470433 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells.

Valencia-González Heriberto Abraham HA Ruíz Graciela G Ortiz-Sánchez Elizabeth E García-Carrancá Alejandro A

Stem cells international 20190403

Recently, a subpopulation of tumor cells, called cancer stem cells (CSC), has been characterized, and these have emerged as a major topic in cancer research. CSC are proposed to repair DNA damage more efficiently than the rest of tumor cells, resisting chemotherapy or radiotherapy and causing clinical recurrence and metastasis. We aimed to determine the molecular basis of radioresistance and first compared the response to ionizing radiation (IR) between cancer stem cell-enriched cultures grown a ...[more]

PMID: 31073313

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Project description:Mitochondria are highly dynamic organelles that respond rapidly to a number of stressors to regulate energy transduction, cell death signaling, and reactive oxygen species generation. We hypothesized that mitochondrial remodeling, comprising both structural and functional alterations, following ionizing radiation (IR) may underlie some of the tenets of radiobiology. Mesenchymal stem cells (MSCs) are precursors of bone marrow stroma and are altered in acute myeloid leukemia and by radiation and chemotherapy. Here, we report on changes in mitochondrial remodeling in human MSCs following X-ray IR. Mitochondrial function was significantly increased in MSCs 4 h after IR as measured by mitochondrial oxygen consumption. Consistent with this elevated functional effect, electron transport chain supercomplexes were also increased in irradiated samples. In addition, mitochondria were significantly, albeit modestly, elongated, as measured by high-throughput automated confocal imaging coupled with automated mitochondrial morphometric analyses. We also demonstrate in fibroblasts that mitochondrial remodeling is required for the adaptation of cells to IR. To determine novel mechanisms involved in mitochondrial remodeling, we performed quantitative proteomics on isolated mitochondria from cells following IR. Label-free quantitative mitochondrial proteomics revealed notable changes in proteins in irradiated samples and identified prosaposin, and potentially its daughter protein saposin-B, as a potential candidate for regulating mitochondrial function following IR. Whereas research into the biologic effects of cellular irradiation has long focused on nuclear DNA effects, our experimental work, along with that of others, is finding that mitochondrial effects may have broader implications in the field of stress adaptation and cell death in cancer (including leukemia) and other disease states.-Patten, D. A., Ouellet, M., Allan, D. S., Germain, M., Baird, S. D., Harper, M.-E., Richardson, R. B. Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation.

Dataset Information

Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells.

Publications

Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells.

Similar Datasets

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