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UNDERSTANDING OF CANCER METABOLIC DISORDERS BY FANCONI ANEMIA SIGNALING PATHWAY

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Title:UNDERSTANDING OF CANCER METABOLIC DISORDERS BY FANCONI ANEMIA SIGNALING PATHWAY
Authors:Nepal, Manoj
Contributors:Fei, Peiwen (advisor)
Molecular Biosciences and Bioengineering (department)
Keywords:Molecular biology
Bioengineering
Aigng
Cancer
Diabetes
show 3 moreFanconi Anemia (FA)
Inflammation
Metabolites
show less
Date Issued:2019
Publisher:University of Hawai'i at Manoa
Abstract:Cancer is a genetic disease, as an outcome of a series of genetic alterations that allow the transformation of human cells from a controllable state of growth into a state of un-controllable. The extremely high cancer incidence associated with the patients suffering from a rare human genetic disease, Fanconi Anemia (FA), demonstrates the important tumor-suppression roles that FA genes play during the course of human tumorigenesis, thereby turning FA into a unique genetic model system to study cancer etiology. In this dissertation, we view this rapidly progressed field of FA research and discuss how human malignancy is attributed to the aberrant FA gene functions. We also highlighted the fanconi anemia signaling in metabolic disorders, and further discussed the impact of activated or impaired FA pathway in metabolic disorders in FA dependent and Independent experimental studies. Growing evidences support a general hypothesis that cancer primarily is a disease of energy metabolism. Extremely high incidence of cancer associated with Fanconi anemia (FA) patients indicates FA is a unique genetic model system to study the etiology of cancer. However, it is barely studied as to the involvement of FA gene products in energy metabolism. We report that a proper mitochondria function in producing ATP is attributed to a fully functioning FA complementation group D2 protein (FANCD2). We found that FANCD2 could interact sufficiently with ATP5α, which is responsible for mitochondria ATP production, and that mutant FANCD2 (K561R) could not. In cells carrying a fully functioning FANCD2, ATP5α locates at mitochondria; however, when cells carry inactivated FANCD2, ATP5α mostly is located outside mitochondria, and the mitochondria ATP production is significantly reduced compared to those cells carrying wtFANCD2. We identified a region (AA42-72) in ATP5α protein, which accounts for the interaction with FANCD2, and the protein docking analysis further validated their interaction. mtATP5α (∆AA42-72) showed its aberrant localization, and cells carrying the given mutant produce a low amount of ATP, similar to what observed in mtFANCD2(K561R)-carrying cells. Collectively, this study demonstrates a previously unknown role of FANCD2 in governing cellular ATP production, at least, by interfering with the function of ATP5α and advances our understanding of how defective FA signaling contributes, at the energy metabolism level, to aging and cancer. In FA pathway independent study, we demonstrated an unbiased and systematic investigation of cellular effect of FA protein in metabolic disorders and found an independent role of Fanconi Anemia group C protein in metabolic disorders such as Aging, Inflammation, Diabetes and Cancer. This study was prompted by the diabetes-prone feature displayed from the FANCC knockout mice, which is not typically shown in patients with FA. We found that in cells expressing FANCC at different levels, there are representative alterations in the metabolites associated with aging (Glycine, Citrulline, Ornithine, L-Asparagine, L-Tyrosine, L-Arginine, L-glutamine, L-Leucine, L-Isoleucine, L-Valine, L-Proline and L-Alanine), Diabetes Mellitus (DM) (carbon monoxide, Collagens, Fatty acids, D-glucose, Fumaric acid, 2-oxoglutaric acid, C3), inflammation (Inosine, L-arginine, L-isoleucine, L-leucine, L-lysine, L-phenylalanine, Hypoxanthine, L-methionine), and cancer ( L-methionine, sphingomyelin, acetyl-L-carnitine, L-aspartic acid, L-glutamic acid, niacinamide, phosphorylethanolamine). We found that FANCC can act in an FA-pathway-independent manner in tumor suppression. Taken together, these specific metabolic alterations are readouts of functional mechanisms underlying the reduced tumorigenicity that was driven by FANCC, demonstrating the crosstalks among cancer, aging, inflammation and Diabetes at the metabolic level.
Description:Ph.D. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019
Pages/Duration:125 pages
URI:http://hdl.handle.net/10125/63210
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Molecular Biosciences and Bioengineering


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