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Proton shifting induces cell growth and is exploited in leukemia by epigenetic enforcement of H+/lactate-cotransporter expression

ABSTRACT: Proton shifting induces cell growth and is exploited in leukemia by epigenetic enforcement of H+/lactate-cotransporter expression

PROVIDER: PRJNA513077 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8397560.fastq.gz	Fastqsanger.gz
	SRR8397560_1.fastq.gz	Fastqsanger.gz
	SRR8397560_2.fastq.gz	Fastqsanger.gz
	SRR8397570.fastq.gz	Fastqsanger.gz
	SRR8397570_1.fastq.gz	Fastqsanger.gz

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Proton shifting induces cell growth and is exploited in leukemia by epigenetic enforcement of H+/lactate-cotransporter expression

Project description:Ion balance is critical for membrane polarity, signaling and bioenergesis in cells. Here, we report that proton distribution resets metabolism and alters growth in hematopoietic cells. Multiple oncogenic mutations in acute myeloid leukemia utilize proton partitioning to enhance growth by epigenetically upregulating H+/lactate-co-transporter, MCT4, shuttling protons extracellularly to increase intracellular pH. Secondarily, activity of metabolic enzymes (hexokinase, pyruvate kinase and glucose-6-phosphate dehydrogenase) is increased, raising carbon flux through glycolysis and pentose phosphate pathway necessary for proliferation. MCT4-overexpression in normal hematopoietic stem and progenitor cells increases growth without malignant transformation. Yet, inhibiting MCT4 in AML decreases pHi and carbon flux that improves animal survival and, unexpectedly, elimination of leukemic initiating cells in vivo. AML with increased MCT4 expression have activating histone mark, H3K27ac, in MCT4 promoter where MLL-AF9 and BRD4 directly bind. These data demonstrate the sequential alteration of metabolism through epigenetic activation of proton regulator and point to cytoplasmic alkalization as a growth promoting strategy exploited by malignant cells. Inhibiting this process may diminish the competitive advantage of leukemia and potentially improve AML treatment.

2020-12-31 | GSE124696 | GEO

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soil from rotational shifting cultivation

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Project description:Literature data report the helpful role of specific molecularly based signatures to predict response to treatment in cancer, including breast cancer (BC) disease. As known, BC is a heterogeneous disease presenting distinct subtypes with different clinical outcomes. Thus, the choice of a unique treatment plan for all BC patients, including radiation therapy (RT), may be not the best option. Technological advances in RT are evolving with the use of proton beams, which reduce the dose administered to the heart compared to conventional RT. However, limitate data regarding proton-induced molecular changes are currently available. The aim of this study was therefore to study gene expression profiles induced by proton irradiation with 0.5, 2 and 9 Gy of Ionizing radiation (IR) doses in breast cells. The great amount of data here collected, represent an useful tool to better understand the molecular mechanisms elicited by proton irradiation, thereby filling the existing lack of data in the literature.

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Project description:We performed comparative RNA sequencing of the early (4 hrs) dose response (0.5 – 200 cGy whole body dose, 10 dose levels) of the mouse aorta to proton and gamma radiation. Total-body proton radiation of conscious animals was performed using a proton beam produced by a cyclotron system, while total-body gamma radiation of animals was performed using a Caesium-137 gamma source. A trend analysis identified genes that showed a dose response, using data permutation to estimate a false discovery rate (q-value) for each gene. We identified 29 and 194 genes (q-value ≤ 0.1) that were upregulated with increasing doses of proton and gamma radiation, respectively. No genes were down-regulated. While fewer genes were dose-responsive to proton radiation, the magnitude of the effect was greater than with gamma radiation. These highly responsive genes were enriched for pathways involved in the response to DNA damage, apoptosis, cellular stress and inflammation (p < 0.01). Gamma radiation responsive genes included the same pathways, but extended to genes in vasculature specific pathways. Genes responsive to both radiation types (19 genes at q-value ≤ 0.1) showed almost perfectly superimposable dose-response relationships. We observed the same superimposable dose response relationship of gamma and proton radiations in a subset of genes validated by quantitative PCR not only in the aorta but also in liver, lung, heart and kidney. Despite a relative similar relative biological effectiveness of protons and gamma photons and the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response. It seems plausible that these genomic differences translate into differences in the biological processes leading to cardiovascular pathologies.

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Project description:Proton irradiation is touted for its improved tumor targeting due to the physical advantages of ion beams for radiotherapy. Recent studies from our laboratory have shown that, in addition to targeting advantages, proton irradiation can inhibit angiogenic and immune factors and thereby modulate tumor progression. High-energy protons also constitute a principal component of the galactic cosmic rays to which astronauts are exposed. Increased understanding of the biological effects of proton exposure would thus contribute to both improved cancer therapy and carcinogenesis risk assessment for space travel. In addition, age plays a major role in tumor incidence and is a critical consideration for estimating cancer risk. We investigated the effects of host age and proton exposure on tumor progression. Tumor lag time and growth dynamics were tracked following injection of murine Lewis lung carcinoma (LLC) cells into young (68 day) versus old (736 day) mice with or without coincident irradiation. Tumor progression was suppressed in old compared to young mice. Differences in progression were further modulated by proton irradiation (1GeV), with increased inhibition evident in old mice. Through global transcriptome analysis, TGFβ1 and TGFβ2 were determined to be key players that contributed to the tumor dynamics observed. These findings point to older hosts providing decreased systemic tumor support, which can be further inhibited by proton irradiation.

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