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AMELIORATION OF CANCER-INDUCED CACHEXIA BY INHIBITION OF NF-êB SIGNALING PATHWAY

Sae-Chew, Pattarana (2009) AMELIORATION OF CANCER-INDUCED CACHEXIA BY INHIBITION OF NF-êB SIGNALING PATHWAY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Cachexia is the most debilitating syndrome which manifests itself in several chronic, life-threatening diseases, especially in cancer. Cachexia is of major public health significance for the cancer population because it increases both morbidity and mortality and also reduces quality of life and survival time of cancer patients. Up to two-thirds of patients with advanced neoplasia develop signs and symptoms of cachexia, including anorexia, asthenia and severe unintentional weight loss leading to immobility and cardiac or respiratory failure. Cachexia accounts for more than 20% of all cancer-associated deaths.In the present study, we established a novel murine model for cancer cachexia induced by the human prostate cancer cell line PC-3. In a novel mouse model of cachexia induced by PC-3 cells, an established androgen-independent cell line derived from a bone metastasis of a human prostatic adenocarcinoma, in BALB/c nude mice we observed body weight loss, a 50% reduction in muscle weights and decreased muscle fiber diameters. Elevated levels of the phosphorylated p65 subunit of the nuclear factor of êB (NF-êB) were found in tibialis anterior and quadriceps muscles, but not in gastrocnemius muscle. Elevated levels of the muscle specific E3 ligase (MuRF1) confirmed activation of the ubiquitin-proteosome protein degradation pathway in these muscles. In contrast, elevated levels of the phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2-á) in gastrocnemius muscle, but not in tibialis anterior and quadriceps muscles, suggested a greater component of cachexia due to decreased protein synthesis in this muscle.We also utilized a well-established murine model of cancer cachexia induced by murine colon adenocarcinoma cell line (C-26). C-26 tumor-bearing mice were treated with an intramuscular injection of an adeno-associated viral vector serotype 8 (AAV8) carrying the IêB super repressor (IêBSR) or cellular caspase-8-like inhibitory protein (cFLIP) gene driven by the cytomegalovirus (CMV) or muscle creatine kinase (MCK) promoter. We found that there was an improvement in body weight, individual muscle weight and muscle fiber diameter in mice receiving AAV8-IêBSR or AAV8-cFLIP. We also observed a reduction of MuRF1 protein expression, indicating that there was a reduction in muscle protein degradation via the ubiquitin-proteasome system. The result was confirmed by an increased level of myosin heavy chain protein expression. This study suggests the potential for AAV8 carrying IBSR gene mediated gene transfer to prevent or reverse cachectic symptoms in vivo.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sae-Chew, Pattaranapattarana@hotmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberRobbins, Paulprobb@pitt.eduPROBB
Committee MemberClemens, Paulaclempr@UPMC.EDU
Committee MemberGollin, Susannegollin@pitt.eduGOLLIN
Date: 28 September 2009
Date Type: Completion
Defense Date: 12 May 2009
Approval Date: 28 September 2009
Submission Date: 3 June 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: AAV; C-26; Cachexia; NF-êB; PC-3
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06032009-195308/, etd-06032009-195308
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44
URI: http://d-scholarship.pitt.edu/id/eprint/8002

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