Oral squamous cell carcinomas comprise of more than ninety percent of malignancies arising from the oral cavity. Despite recent advances in the past decades, the prognosis in patients remains poor. Better understanding of the complexity of impaired cell growth regulatory elements among these tumors may provide important novel avenues for targeting cancer therapy. The long-term goal of this project is to explore the use of PPAR-gamma signaling pathway as a target for drug therapy in head and neck squamous cell carcinoma. Specifically, the present proposal seeks to establish that activation of FADD-mediated Fas (Fas, CD95, APO-1) apoptosis pathway by peroxisome proliferator-activated receptor-gamma (PPARgamma) signaling underlies an important apoptotic attribute of PPARgamma in oral squamous cell carcinoma. Several signaling pathways, notably phosphatidylinositol 3-kinase and downstream protein kinase B (P13-K/Akt) play a crucial role in evading Fas-mediated tumor cell death. Thus, this hypothesis also seeks to prove that PPARgamma interacts with (P13-K/Akt) signaling pathway to further exert its role in activation of Fas-mediated apoptosis. To test this hypothesis, a molecular approach, including Real-Time PCR, Western Blot, gel shift assays, apoptosis assays, transfection studies, gene knockout, and over-expression vectors will be used to demonstrate the direct role of PPARgamma in mediating tumor cell growth through interaction with Fas and P13-k/Akt pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE014935-03
Application #
6892805
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Avila, Albert
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$34,981
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Siavash, H; Nikitakis, N G; Sauk, J J (2004) Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ(2) in oral squamous carcinoma cells. Br J Cancer 91:1074-80
Nikitakis, N G; Siavash, H; Sauk, J J (2004) Targeting the STAT pathway in head and neck cancer: recent advances and future prospects. Curr Cancer Drug Targets 4:637-51
Siavash, H; Nikitakis, N G; Sauk, J J (2004) Signal transducers and activators of transcription: insights into the molecular basis of oral cancer. Crit Rev Oral Biol Med 15:298-307