國立虎尾科技大學 |

Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation : = Examining the Interplay of Gasotransmitters and Glutaminolysis.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation :/
Reminder of title:	Examining the Interplay of Gasotransmitters and Glutaminolysis.
Author:	Xing, Dianna L.
Description:	1 online resource (207 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
Subject:	Biochemistry. -
Online resource:	click for full text (PQDT)
ISBN:	9798380306997

Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation : = Examining the Interplay of Gasotransmitters and Glutaminolysis.
Xing, Dianna L.

Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation :Examining the Interplay of Gasotransmitters and Glutaminolysis. - 1 online resource (207 pages)

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2023.

Includes bibliographical references

Oxidative phosphorylation is an oxygen-dependent metabolic process that provides the majority of ATP used to support essential cellular functions. However, in cancer, limitations in oxygen availability occur during the development and metastasis of tumors. To compensate for the demands of rapidly proliferating cells, many cancers exhibit an increased demand for glycolysis, the TCA cycle, and glutaminolysis. In this thesis, extracellular flux technology and metabolomics were applied in a hypoxia-reoxygenation model to investigate the metabolic adaptations that occur in dynamic changes in oxygen and nutrient availability in cancer cells. We show the significance of glutaminolysis and its substrates in regulating cancer cell bioenergetics and survival in hypoxia-reoxygenation through 1) restricting L-glutamine (L-gln) availability to inhibit oxygen-sensing pathways during hypoxia and damaging mitochondrial Complex I (CI) activity in the electron transport chain (ETC) and, 2) supplementing media with α-ketoglutarate (α-KG) in place of L-gln to partially rescue oxygen-sensing, mitochondrial bioenergetics, CI activity, and viability. To further examine the influence of environmental factors, secondary modifiers of metabolism, nitric oxide (NO) and hydrogen sulfide (H2S), were implemented in our model. These gaseous molecules demonstrated differential effects on mitochondria, with NO showing anti-cancer effects at high doses administered by NO-donor compound, DetaNONOate. The relationship between bioenergetics, α-KG availability, and other adjacent L-gln-dependent pathways were assessed such as glutathione (GSH) synthesis. Buthionine sulfoximine, an experimental anti-cancer compound, was used to inhibit GSH synthesis. Although glutaminolysis was not found to be a major contributor to GSH synthesis, α-KG was found to partially protect this process, and GSH aided in protecting mitochondria from reoxygenation damage. Lastly, contributions of CI in regulating electron flux during hypoxia and producing mitochondrially damaging ROS were tested using rotenone, an inhibitor of CI. Our findings revealed α-KG partially reversed pharmacological inhibition of CI and continued to offer partial protection from mitochondrial damage after hypoxia-reoxygenation. Taken together, this work presents novel observations regarding the role of TCA cycle metabolites, L-gln and α-KG, in regulating and protecting mitochondria from oxygen and nutrient limitations in the progression of cancer and may provide a basis for metabolically targeted therapies in treating cancer.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380306997Subjects--Topical Terms:

582831
Biochemistry.
Subjects--Index Terms:

BioenergeticsIndex Terms--Genre/Form:

554714
Electronic books.

Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation : = Examining the Interplay of Gasotransmitters and Glutaminolysis.
LDR:04070ntm a22004217 4500 001 1149330
005 20241015112516.5
006 m o d
007 cr bn ---uuuuu
008 250605s2023 xx obm 000 0 eng d
020 $a 9798380306997
035 $a (MiAaPQ)AAI30526704
035 $a AAI30526704
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Xing, Dianna L. $3 1475519
245 1 0 $a Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation : $b Examining the Interplay of Gasotransmitters and Glutaminolysis.
264 0 $c 2023
300 $a 1 online resource (207 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
500 $a Advisor: Darley-Usmar, Victor.
502 $a Thesis (Ph.D.)--The University of Alabama at Birmingham, 2023.
504 $a Includes bibliographical references
520 $a Oxidative phosphorylation is an oxygen-dependent metabolic process that provides the majority of ATP used to support essential cellular functions. However, in cancer, limitations in oxygen availability occur during the development and metastasis of tumors. To compensate for the demands of rapidly proliferating cells, many cancers exhibit an increased demand for glycolysis, the TCA cycle, and glutaminolysis. In this thesis, extracellular flux technology and metabolomics were applied in a hypoxia-reoxygenation model to investigate the metabolic adaptations that occur in dynamic changes in oxygen and nutrient availability in cancer cells. We show the significance of glutaminolysis and its substrates in regulating cancer cell bioenergetics and survival in hypoxia-reoxygenation through 1) restricting L-glutamine (L-gln) availability to inhibit oxygen-sensing pathways during hypoxia and damaging mitochondrial Complex I (CI) activity in the electron transport chain (ETC) and, 2) supplementing media with α-ketoglutarate (α-KG) in place of L-gln to partially rescue oxygen-sensing, mitochondrial bioenergetics, CI activity, and viability. To further examine the influence of environmental factors, secondary modifiers of metabolism, nitric oxide (NO) and hydrogen sulfide (H2S), were implemented in our model. These gaseous molecules demonstrated differential effects on mitochondria, with NO showing anti-cancer effects at high doses administered by NO-donor compound, DetaNONOate. The relationship between bioenergetics, α-KG availability, and other adjacent L-gln-dependent pathways were assessed such as glutathione (GSH) synthesis. Buthionine sulfoximine, an experimental anti-cancer compound, was used to inhibit GSH synthesis. Although glutaminolysis was not found to be a major contributor to GSH synthesis, α-KG was found to partially protect this process, and GSH aided in protecting mitochondria from reoxygenation damage. Lastly, contributions of CI in regulating electron flux during hypoxia and producing mitochondrially damaging ROS were tested using rotenone, an inhibitor of CI. Our findings revealed α-KG partially reversed pharmacological inhibition of CI and continued to offer partial protection from mitochondrial damage after hypoxia-reoxygenation. Taken together, this work presents novel observations regarding the role of TCA cycle metabolites, L-gln and α-KG, in regulating and protecting mitochondria from oxygen and nutrient limitations in the progression of cancer and may provide a basis for metabolically targeted therapies in treating cancer.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2024
538 $a Mode of access: World Wide Web
650 4 $a Biochemistry. $3 582831
650 4 $a Cellular biology. $3 1148666
650 4 $a Oncology. $3 593951
650 4 $a Genetics. $3 578972
653 $a Bioenergetics
653 $a Glutaminolysis
653 $a Hydrogen sulfide
653 $a Hypoxia
653 $a Mitochondria
653 $a Nitric oxide
655 7 $a Electronic books. $2 local $3 554714
690 $a 0487
690 $a 0379
690 $a 0992
690 $a 0369
710 2 $a ProQuest Information and Learning Co. $3 1178819
710 2 $a The University of Alabama at Birmingham. $b Pathology. $3 1475520
773 0 $t Dissertations Abstracts International $g 85-03B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30526704 $z click for full text (PQDT)