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CASPASE-3 PROMOTES CELL PROLIFERATION AND INHIBITS DNA-DAMAGE INDUCED NECROSIS IN COLORECTAL CANCER

Brown, Matthew F (2013) CASPASE-3 PROMOTES CELL PROLIFERATION AND INHIBITS DNA-DAMAGE INDUCED NECROSIS IN COLORECTAL CANCER. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Colorectal cancer leads to over 50,000 deaths in the United States each year. Many colon cancer patients are diagnosed at late stages where surgical options are limited and require chemo- and or radiotherapy. A hallmark of cancer is the accumulation of genetic mutations resulting in dysfunction of the apoptotic response, which can lead to reduced sensitivity to chemo- and radiotherapy. Damaged cells can also die through necrosis, previously thought to be an unregulated process. Recent studies have begun to suggest that necrosis is an orderly event that occurs in cells when apoptosis is blocked, and kinases, rather than p53, play a critical role in activating downstream necrotic machinery. The high incidence of p53 mutation and apoptotic dysfunction in cancer requires development of new treatment strategies, with activation of necrosis a potentially beneficial option. However, little is known about the relationship between different forms of cell death and how it is regulated.
Caspases are cysteine proteases best known to play a pivotal role in the execution of apoptosis. However, recent studies indicate roles beyond apoptosis. Interestingly, Caspase-8 inhibits autophagy and necrosis, whereas caspase-3 promotes survival of cancer cells following radiation therapy. In an effort to determine the role of caspase-3 in colon cancer cell survival and proliferation, we generated caspase-3 knockout HCT-116 colon cancer cells using recombinant adeno-associated virus (AAV)-mediated gene targeting. Interestingly, we observe an unexpected decrease in proliferation and altered mitochondrial morphology in caspase-3 knockout cells, compared to wild-type cells. Furthermore, caspase-3 knockout cells exhibit reduced oxidative phosphorylation and increased glutamine dependence. In addition to altered metabolism, caspase-3 knockout cells are more sensitive to DNA damaging agents, including 5-FU, etoposide and camptothecin due to an increase in programmed necrosis. This is in stark contrast to wild-type cells that die largely via apoptosis. Having shown that caspase-3 promotes survival and proliferation of colon cancer cells and reduces sensitivity to multiple DNA damaging agents we hypothesize that targeting its non-apoptotic functions may improve the effectiveness of chemotherapeutic agents.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brown, Matthew Fmfb20@pitt.eduMFB20
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorYu, Jian yuj2@upmc.edu
Committee ChairMonga, Satdarshan P. S.smonga@pitt.eduSMONGA
Committee MemberZarnegar, Reza REZAZAR@pitt.eduREZAZAR
Committee MemberSobol, Robert Wrws9@pitt.eduRWS9
Committee MemberXiao, Gutian xiaog2@upmc.edu
Date: 10 December 2013
Date Type: Publication
Defense Date: 3 December 2013
Approval Date: 10 December 2013
Submission Date: 10 December 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 184
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cancer Caspase-3 Colorectal Cancer Chemotherapeutics 5-fluorouracil DNA Damage Necrosis
Date Deposited: 10 Dec 2013 18:31
Last Modified: 15 Nov 2016 14:16
URI: http://d-scholarship.pitt.edu/id/eprint/20234

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