Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Lall, Rajuli; Ganapathy, Suthakar; Yang, Mei; Xiao, Shan; Teng, Xu; Su, Hang; Shadfan, Miriam; Asara, John M.; Ha, Chul S.; Ben-Sahra, Issam; Manning, Brendan D.; Little, John B.; Yuan, Zhi Min

doi:10.1038/cdd.2014.24

Cited by 78 publications

(64 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A potential molecular mechanism that could facilitate the MUC1-induced metabolic reprogramming could be through HIF-1α. Low dose irradiation enhances HIF-mediated metabolic responses as reported in a recent study (49) and our previous study showed that MUC1-mediated HIF-1α stabilization leads to upregulation of glycolytic and PPP metabolic pathway genes in MUC1-expressing pancreatic cancer cells (18). Our results establish that metabolic responses elicited in MUC1-expressing cells can be effectively targeted using BrPA, which reduces radiation-resistance in pancreatic cancer cells.…”

Section: Discussionsupporting

confidence: 55%

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

Gunda

Souchek

Abrego

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose MUC1, an oncogene overexpressed in multiple solid tumors including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models. Experimental design We used MUC1 knockdown and overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response and metabolomic evaluations. We also investigated if inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance using in vitro and in vivo models. Results MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pre-treatment with the glycolysis inhibitor, 3-bromopyruvate (BrPA) abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pre-treatment with nucleoside pools. Conclusions MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation-resistance in pancreatic cancer and targeted effectively through glycolytic inhibition.

show abstract

Section: Discussionsupporting

confidence: 55%

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

Gunda

Souchek

Abrego

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…For cells and animals, low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis, leading to increased resistance to radiation [42]. In normal cells, a low-oxygen environment generally induces glycolysis [6].…”

Section: Discussionmentioning

confidence: 99%

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

show abstract

“…Although mitochondrial remodeling has been observed and proven protective across a number of different stressors (13–15), its potential role in modulating the adaptive response had previously been uncharacterized. Interestingly, Lall et al (61) described an HIF1-dependent metabolic adaptation at 5% O 2 to the adaptive response that involves the induction of a glycolytic program at later time points (12 h). We believe that this adaptation may be attributed to changes in the radiation oxygen effect, in which greater cell death is observed at higher O 2 tension, as previously described by Richardson and Harper (3).…”

Section: Discussionmentioning

confidence: 99%

“…Our system differs from that of Lall et al . (61) in that experiments were performed at 21% O 2 and the IR adaptation was observed at short time points postirradiation. Taken together, it could be speculated that 2 metabolic processes may regulate the adaptive response at different time points: first, in the short term, mitochondrial remodeling increases metabolic efficiency and ATP production, and secondly, in the longer term, processes induce a metabolic shift toward glycolysis (62, 63), which may limit the damaging ROS production from mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

et al. 2019

View full text Add to dashboard Cite

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. FASEB J. 33, 9263–9278 (2019). http://www.fasebj.org

show abstract

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Cited by 78 publications

References 35 publications

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

Contact Info

Product

Resources

About