東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

Regulating Cancer Cell Metabolism Du...

Xing, Dianna L.

Linked to FindBook

Google Book

Amazon

博客來

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

Record Type:	Electronic resources : Monograph/item
Title/Author:	Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation: Examining the Interplay of Gasotransmitters and Glutaminolysis./
Author:	Xing, Dianna L.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	207 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
Subject:	Biochemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30526704
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. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 207 p.

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

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

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.

ISBN: 9798380306997Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Bioenergetics

Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation: Examining the Interplay of Gasotransmitters and Glutaminolysis.
LDR:03868nmm a2200421 4500 001 2401076
005 20241015112516.5
006 m o d
007 cr#unu||||||||
008 251215s2023 ||||||||||||||||| ||eng d
020 $a 9798380306997
035 $a (MiAaPQ)AAI30526704
035 $a AAI30526704
035 $a 2401076
040 $a MiAaPQ $c MiAaPQ
100 1 $a Xing, Dianna L. $3 3771138
245 1 0 $a Regulating Cancer Cell Metabolism During Hypoxia-Reoxygenation: Examining the Interplay of Gasotransmitters and Glutaminolysis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2023
300 $a 207 p.
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.
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.
590 $a School code: 0005.
650 4 $a Biochemistry. $3 518028
650 4 $a Cellular biology. $3 3172791
650 4 $a Oncology. $3 751006
650 4 $a Genetics. $3 530508
653 $a Bioenergetics
653 $a Glutaminolysis
653 $a Hydrogen sulfide
653 $a Hypoxia
653 $a Mitochondria
653 $a Nitric oxide
690 $a 0487
690 $a 0379
690 $a 0992
690 $a 0369
710 2 $a The University of Alabama at Birmingham. $b Pathology. $3 1684960
773 0 $t Dissertations Abstracts International $g 85-03B.
790 $a 0005
791 $a Ph.D.
792 $a 2023
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30526704