Apoptosis is programmed cell death, which is characterized by condensation of the nucleus and cytoplasm, specific protein degradation, and DNA fragmentation. Extensive studies have documented that apoptosis is the primary killing mechanism induced by cancer therapies such as chemotherapy, radiotherapy or the cell death factor TNFalpha. Oral cancer is a widely distributed cancer which is typified by squamous cell carcinoma (SCC). Importantly, SCC is very resistant to cancer therapy and TNFalpha, but the genetic and molecular mechanisms underlying this resistance are complex and poorly understood. Our preliminary studies from in vitro and in vivo presented in this application indicate that NF-kB is a pro-survival transcription factor for oral squamous cell carcinoma and inhibition of NF-kB renders SCC sensitive to TNFalpha-mediated apoptosis. Using TNFalpha as death inducer, the cell death machinery of SCC will be systematically dissected, and the molecular mechanism of NF-kB anti-apoptosis will be explored.
The specific aims proposed in this application are to: 1) Determine the primary mechanisms of SCC resistance to TNFalpha-mediated apoptosis by examining how NF-kB inducible anti-apoptotic genes inhibit caspase-8 activation; 2) Explore whether activation of NF-kB directly regulates TNFalpha-mediated apoptosis at the level of mitochondria in SCC, focusing on the role of NF-kB regulated A1 and manganese superoxide dismutase (MSN) proteins in inhibition of the release of cytochrome c; 3) Determine the expression of NF-kB inducible anti-apoptotic genes in SCC in vivo by immunohistochemistry, and thereby explore whether the aberrant expression of specific anti-apoptotic genes is related to the development of SCC; and 4) Identify potential regulators of apoptosis of SCC by functional cloning, and explore the potential role of these regulators in the development of SCC. These studies will elucidate the intrinsic genetic and molecular mechanism of cell resistance to TNFalpha-mediated apoptosis. Importantly, these studies will help to develop the biological marker for the diagnosis of oral cancer and provide a molecular basis for improving efficacy of cancer therapy by manipulating the apoptotic program of oral cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013848-02
Application #
6350621
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
2000-02-01
Project End
2005-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$266,710
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Li, Jiong; Chen, Xiaohong; Ding, Xiangming et al. (2013) LATS2 suppresses oncogenic Wnt signaling by disrupting ?-catenin/BCL9 interaction. Cell Rep 5:1650-63
Ramadoss, Sivakumar; Li, Jiong; Ding, Xiangming et al. (2011) Transducin ?-like protein 1 recruits nuclear factor ?B to the target gene promoter for transcriptional activation. Mol Cell Biol 31:924-34
Tang, Eric D; Wang, Cun-Yu (2010) TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. PLoS One 5:e9172
Kim, Jinkoo; Guan, Jean; Chang, Insoon et al. (2010) PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells. Mol Cancer Ther 9:1977-84
Krum, Susan A; Chang, Jia; Miranda-Carboni, Gustavo et al. (2010) Novel functions for NF?B: inhibition of bone formation. Nat Rev Rheumatol 6:607-11
Rehman, Aasia O; Wang, Cun-yu (2009) CXCL12/SDF-1 alpha activates NF-kappaB and promotes oral cancer invasion through the Carma3/Bcl10/Malt1 complex. Int J Oral Sci 1:105-18
Chang, Jia; Wang, Zhuo; Tang, Eric et al. (2009) Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med 15:682-9
Rehman, Aasia O; Wang, Cun-Yu (2008) SDF-1alpha promotes invasion of head and neck squamous cell carcinoma by activating NF-kappaB. J Biol Chem 283:19888-94
Fribley, Andrew; Wang, Cun-Yu (2006) Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. Cancer Biol Ther 5:745-8
Fribley, Andrew M; Evenchik, Benjamin; Zeng, Qinghua et al. (2006) Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem 281:31440-7

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