• Login
    View Item 
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UA Campus RepositoryCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournalThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournal

    My Account

    LoginRegister

    About

    AboutUA Faculty PublicationsUA DissertationsUA Master's ThesesUA Honors ThesesUA PressUA YearbooksUA CatalogsUA Libraries

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Bone-Specific Metabolism and Mechanism of Action of Curcuminoids in Blocking Osteolysis in Breast Cancer and Other Resorptive Bone Diseases

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    azu_etd_17598_sip1_m.pdf
    Embargo:
    2022-01-03
    Size:
    15.14Mb
    Format:
    PDF
    Download
    Author
    Kunihiro, Andrew
    Issue Date
    2019
    Keywords
    cancer
    curcumin
    metastasis
    Advisor
    Funk, Janet L.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 01/03/2022
    Abstract
    Osteoclast-mediated bone resorptive disorders, including post-menopausal osteoporosis, age-related bone loss, rheumatoid arthritis, and osteolytic bone metastases, affect over 55 million Americans each year. Breast cancer bone metastases, the model of bone resorptive disorders to be used here, causes osteolysis through a “vicious cycle”, whereby osteoclasts release growth factors (e.g., TGFβ) stored in the bone, which can cause bone-metastatic tumor cells to secrete pro-osteolytic factors (e.g., PTHrP), resulting in more osteoclast-mediated bone resorption. Curcuminoids, dietary polyphenols derived from the turmeric rhizome, inhibit progression of osteolytic bone metastases and other resorptive diseases by targeting osteoclasts and – in the case of bone metastases, also blocking tumoral TGFβ signaling – despite circulating as a glucuronide conjugate that is posited to lack bioactivity. These studies demonstrated that curcumin-glucuronide did not inhibit tumoral TGFβ signaling, with confirmation in multiple breast cancer cell lines that form TGFβ-dependent osteolytic lesions, nor did it inhibit osteoclastogenesis, with both TGFβ signaling and osteoclastogenesis being central to this osteolytic feed-forward loop. However, mouse bone marrow β-glucuronidase (GUSB) deconjugated curcumin-glucuronide to the active aglycone, which was maintained across sexual and skeletal development and with bone resorptive disorders, with evidence that human bone marrow also has deconjugation activity. Other bone-protective dietary polyphenols (e.g., quercetin and resveratrol) were also deconjugated by bone marrow, a GUSB-mediated effect that was required for bone-protective bioactivity, suggesting that GUSB-mediated deconjugation of abundantly glucuronidated dietary polyphenols may be a universal requirement to derive benefits. Finally, curcuminoids inhibited tumoral TGFβ signaling by reducing protein levels of TGFβR2 (receptor that binds TGFβ) and Smad2 (phosphorylated by TGFβR1 following activation of TGFβR2 to stimulate genes promoting bone metastasis progression) primarily through effects on gene expression that depended, in part, on oxidative metabolism. In toto, these novel findings answer a long-standing question about curcumin’s apparent lack of bioavailability, with implications for the bioactivity of other dietary polyphenols, and provide a framework for future studies to explore how interindividual GUSB expression in the population may impact both curcumin’s bone-protective bioactivity and its side effects as well as to further provide insight into cellular targets underlying curcumin’s inhibition of signaling pathways important in bone resorption.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Nutritional Sciences
    Degree Grantor
    University of Arizona
    Collections
    Dissertations

    entitlement

     
    The University of Arizona Libraries | 1510 E. University Blvd. | Tucson, AZ 85721-0055
    Tel 520-621-6442 | repository@u.library.arizona.edu
    DSpace software copyright © 2002-2017  DuraSpace
    Quick Guide | Contact Us | Send Feedback
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.