Elucidating cellular signaling mechanisms of anoikis resistance
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Ng, Tony Ling Tin
issued: 2014-04-22T16:34:19Z
issued: 2014
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Anoikis, which describes a physiologic apoptotic mechanism of non-hematopoietic cells that is triggered following detachment of cells from their native extracellular matrix, functions as a key process to prevent unwanted dissemination of cells from their intended organ site. Cancer cells, in contrast, develop mechanisms to suppress anoikis, allowing them to metastasize through the lymphovascular system to secondary organ sites. In this thesis, we utilized screening methodologies to identify novel signaling mechanisms of anoikis resistance in cancer cells. While a functional approach using an siRNA-based screen of Ewing sarcoma cells did not yield validatable hits, use of gene expression profiling demonstrated a remarkable resemblance of the cellular detachment process to various prototypical forms of cellular and bioenergetic stress, such as nutrient deprivation, hypoxia and endoplasmic reticulum stress. Correspondingly, activation of various cellular stress response pathways was demonstrated, which appear critical for mitigating this stress. In particular, two pathways were shown to play a role in anoikis resistance, mediated by TXNIP and AMPK. TXNIP, which has been shown to play a homeostatic role to modulate glucose metabolism, redox status and proliferation during stress states, was shown to be rapidly up-regulated following cellular detachment, and promotes anoikis in certain cell line models. AMPK is also rapidly activated, activating multiple downstream pathways to restore the bioenergetic status of detached cells, which show marked reduction in ATP levels following detachment. In particular, AMPK-mediated suppression of the mTORC1 pathway plays a particularly important role through the suppression of total protein synthesis levels, an otherwise energetically-costly anabolic process. Blockade of the AMPK pathway or restoration of mTORC1 activation in cancer cells help to restore anoikis, while direct inhibition of protein synthesis in AMPK-deficient cancer ce…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/46545
note: Elucidating cellular signaling mechanisms of anoikis resistance by Tony Ling Tin Ng B.Sc., Simon Fraser University, 2002 M.D., The University of British Columbia, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2014 © Tony Ling Tin Ng 2014 ii Abstract Anoikis, which describes a physiologic apoptotic mechanism of non-hematopoietic cells that is triggered following detachment of cells from their native extracellular matrix, functions as a key process to prevent unwanted dissemination of cells from their intended organ site. Cancer cells, in contrast, develop mechanisms to suppress anoikis, allowing them to metastasize through the lymphovascular system to secondary organ sites. In this thesis, we utilized screening methodologies to identify novel signaling mechanisms of anoikis resistance in cancer cells. While a functional approach using an siRNA-based screen of Ewing sarcoma cells did not yield validatable hits, use of gene expression profiling demonstrated a remarkable resemblance of the cellular detachment process to various prototypical forms of cellular and bioenergetic stress, such as nutrient deprivation, hypoxia and endoplasmic reticulum stress. Correspondingly, activation of various cellular stress response pathways was demonstrated, which appear critical for mitigating this stress. In particular, two pathways were shown to play a role in anoikis resistance, mediated by TXNIP and AMPK. TXNIP, which has been shown to play a homeostatic role to modulate glucose metabolism, redox status and proliferation during stress states, was shown to be rapidly up-regulated following cellular detachment, and promotes anoikis in certain cell line models. AMPK is also rapidly activated, activating multiple downstream pathways to restore the bioenergetic status of detached cells, w…
has type: Thesis/Dissertation
date issued: 2014-05
is shown at: 10.14288/1.0103433
language: eng
degree discipline: Pathology and Laboratory Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivs 2.5 Canada
rights URI: http://creativecommons.org/licenses/by-nc-nd/2.5/ca/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/46545