Fibronectin (FN) and its receptors are important regulatory components in tumor cell survival. We have determined that the carboxyl-terminal heparin-binding domain and alternatively spliced V region of FN are important to this process, since a FN miniprotein (V+H-) containing a mutated heparin-binding domain and the V region of FN induces apoptosis of squamous cell carcinoma (SCC) cells. In contrast, the counterpart wildtype protein (V+H+) or other FN miniproteins not containing the V region promote survival of these cells. Furthermore, in SCC cells, the rate of V+H--mediated apoptosis is delayed compared to normal primary keratinocytes. These data suggest that tumorigenicity has enabled the SCC cells to delay their onset of apoptosis in response to an altered matrix, and that the V region and heparin-binding domain of FN regulate survival of these cells. Our preliminary data suggest that the mechanism by which the V+H- protein induces delayed SCC cell apoptosis may involve chondroitin sulfate proteoglycan and integrin receptors, and p53 and c-myc mediated signals. In primary fibroblasts, this apoptotic mechanism is mediated by a chondroitin sulfate proteoglycan, the alpha4 integrin, and by an intriguing new pathway that requires downregulation of p53 and c-myc. In addition, since p53 relocalizes from the nucleus to the cell membrane in this mechanism, and since the integrin-associated signaling molecule focal adhesion kinase (pp125FAK) and c-Jun N-terminal kinase (JNK) are depressed in this pathway, this suggests that p53 may communicate with integrin/FAK generated signals. We posit that SCC cells resist apoptosis in response to an altered FN matrix (V+H-) via cell surface proteoglycan and integrin receptors. This initiates a signal transduction pathway that leads to downregulation of FAK, p53 and c-myc. Secondarily, because of its important role in regulating SCC cell invasion, migration, and apoptosis, we posit that the V region of FN may be important to SCC cell pathogenesis. We will test these hypotheses in the following Specific Aims: (1) Identify the SCC cell-surface receptors involved in delaying apoptosis induced by the V+H- FN protein in these cells and compare these receptors to those present in primary keratinocytes. (2) Examine the SCC cell signaling response involved in delaying apoptosis induced by the V+H- FN protein. (3) Examine the expression of the alternatively spliced V region of FN in low grade and high-grade oral dysplasia and oral cancer. These studies will help explain some of the cell-matrix interactions and signaling mechanisms that regulate tumor cell biology, and may provide insights into the pathogenesis of oral SCC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014429-02
Application #
6949169
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
2004-09-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$327,038
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kamarajan, Pachiyappan; Shin, Jae M; Qian, Xu et al. (2013) ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC. Cancer Med 2:793-802
Kamarajan, Pachiyappan; Alhazzazi, Turki Y; Danciu, Theodora et al. (2012) Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of anoikis and tumorigenesis. Cancer 118:5800-10
Tripathi, Pratima; Kamarajan, Pachiyappan; Somashekar, Bagganahalli S et al. (2012) Delineating metabolic signatures of head and neck squamous cell carcinoma: phospholipase A2, a potential therapeutic target. Int J Biochem Cell Biol 44:1852-61
Alhazzazi, Turki Y; Kamarajan, Pachiyappan; Joo, Nam et al. (2011) Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 117:1670-8
Bunek, J; Kamarajan, P; Kapila, Y L (2011) Anoikis mediators in oral squamous cell carcinoma. Oral Dis 17:355-61
Somashekar, Bagganahalli S; Kamarajan, Pachiyappan; Danciu, Theodora et al. (2011) Magic angle spinning NMR-based metabolic profiling of head and neck squamous cell carcinoma tissues. J Proteome Res 10:5232-41
Alhazzazi, Turki Y; Kamarajan, Pachiyappan; Verdin, Eric et al. (2011) SIRT3 and cancer: tumor promoter or suppressor? Biochim Biophys Acta 1816:80-8
Kamarajan, Pachiyappan; Bunek, Julius; Lin, Yong et al. (2010) Receptor-interacting protein shuttles between cell death and survival signaling pathways. Mol Biol Cell 21:481-8
Kamarajan, Pachiyappan; Garcia-Pardo, Angeles; D'Silva, Nisha J et al. (2010) The CS1 segment of fibronectin is involved in human OSCC pathogenesis by mediating OSCC cell spreading, migration, and invasion. BMC Cancer 10:330
Kamarajan, Pachiyappan; Kapila, Yvonne L (2007) An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. Apoptosis 12:2221-31

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