Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells

Tsui, Ke‐Hung; Chung, Li-Chuan; Wang, Shyi-Wu; Feng, Tsui-Hsia; Chang, Phei‐Lang; Juang, Horng‐Heng

doi:10.1530/jme-13-0090

Cited by 35 publications

(30 citation statements)

References 44 publications

(55 reference statements)

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“…Those enzymes include phosphofructokinase, phosphoglycerate mutase, pyruvate kinase, 6-phosphogluconate dehydrogenase, pyruvate dehydrogenase and aconitase39404142434445. Previously unknown regulation events include a retention of glucose-6-phosphate, an increased production rate of PRPP (5-Phospho-alpha-D-ribose 1-diphosphate) and a strongly accelerated production of glyceraldehyde 3-phosphate.…”

Section: Resultsmentioning

confidence: 99%

The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

Diener

Muñoz-Gonzalez

Encarnación

et al. 2016

Sci Rep

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During the transition from a healthy state to a cancerous one, cells alter their metabolism to increase proliferation. The underlying metabolic alterations may be caused by a variety of different regulatory events on the transcriptional or post-transcriptional level whose identification contributes to the rational design of therapeutic targets. We present a mechanistic strategy capable of inferring enzymatic regulation from intracellular metabolome measurements that is independent of the actual mechanism of regulation. Here, enzyme activities are expressed by the space of all feasible kinetic constants (k-cone) such that the alteration between two phenotypes is given by their corresponding kinetic spaces. Deriving an expression for the transformation of the healthy to the cancer k-cone we identified putative regulated enzymes between the HeLa and HaCaT cell lines. We show that only a few enzymatic activities change between those two cell lines and that this regulation does not depend on gene transcription but is instead post-transcriptional. Here, we identify phosphofructokinase as the major driver of proliferation in HeLa cells and suggest an optional regulatory program, associated with oxidative stress, that affects the activity of the pentose phosphate pathway.

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Section: Resultsmentioning

confidence: 99%

The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

Diener

Muñoz-Gonzalez

Encarnación

et al. 2016

Sci Rep

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“…In contrast, activation of SREBP-2 mainly activates transcription of cholesterol biosynthesis genes (Pai et al 1998, Horton et al 2003). Importantly, FAS expression is increased under hypoxia (Tsui et al 2013, Furuta et al 2008), and hypoxia up-regulates the synthesis of SREBP-1, but not SREBP-2 (Li et al 2007, Furuta et al 2008). Putative involvement of SREBP-1 in this regulation is consistent with our finding that synthesis of all acyl-containing lipid classes, but not Ch was increased in neurons under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia

Brose

Marquardt

Golovko

2013

Journal of Neurochemistry

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Hypoxia is involved in many neuronal and non-neuronal diseases, and defining the mechanisms for tissue adaptation to hypoxia is critical for the understanding and treatment of these diseases. One mechanism for tissue adaptation to hypoxia is increased glutamine and/or glutamate (Gln/Glu) utilization. To address this mechanism, we determined total Gln/Glu incorporation into lipids and fatty acids in both primary neurons and a neuronal cell line under normoxic and hypoxic conditions and compared this to non-neuronal primary cells and non-neuronal cell lines. Incorporation of Gln/Glu into total lipids was dramatically and specifically increased under hypoxia in neuronal cells including both primary (2.0- and 3.0- fold for Gln and Glu, respectively) and immortalized cultures (3.5- and 8.0- fold for Gln and Glu, respectively), and 90% to 97% of this increase was accounted for by incorporation into fatty acids (FA) depending upon substrate and cell type. All other non-neuronal cells tested demonstrated decreased or unchanged FA synthesis from Gln/Glu under hypoxia. Consistent with these data, total FA mass was also increased in neuronal cells under hypoxia that was mainly accounted for by the increase in saturated and monounsaturated FA with carbon length from 14 to 24. Incorporation of FA synthesized from Gln/Glu was increased in all major lipid classes including cholesteryl esters, TAGs, DAGs, free FA, and phospholipids, with the highest rate of incorporation into TAGs. These results indicate that increased FA biosynthesis from Gln/Glu followed by esterification may be a neuronal specific pathway for adaptation to hypoxia.

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“…It was shown that HIF1α generally upregulates lactate dehydrogenase A, mitochondrial aconitase, and more specifically fatty acid synthase in high grade tumors [192]. Corroborating this result -arrestin 1 is up-regulated in high grade prostate cancer and stabilizes HIF1α, which is connected to a reduction of succinate dehydrogenase A, fumarate hydratase, dihydrolipoamide dehydrogenase, dihydrolipoyl transacetylase and pyruvate dehydrogenase [193].…”

Section: Genetic Drivers Signaling and Microenvironment In Prostate mentioning

confidence: 94%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

et al. 2015

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells

Cited by 35 publications

References 44 publications

The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia

Organ-Specific Cancer Metabolism and Its Potential for Therapy

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