This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Chemotherapeutic drugs as cisplatin, 5-fluorouracil (5-FU) and docetaxol are the most widely used and effective agents in the treatment of advanced head and neck squamous cell carcinoma (SCC). However, failure of tumors to respond to treatment or tumor recurrence limits the overall success of these therapeutic approaches. Our long-term goal is to identify novel targets for therapeutic intervention by dissecting the molecular mechanism of how the RNA-binding protein La contributes to chemotherapy resistance in oral cancer. The La protein is a RNA chaperone, known to regulate mRNA translation of a number of cellular proteins. Our preliminary data demonstrate, that overexpressed La correlates with protection against cisplatin-induced apoptosis and increased XIAP expression in oropharyngeal SCC cells. XIAP is a well-known inhibitor of programmed cell death (apoptosis). It is overexpressed in various types of cancer, including oral cancer, and contributes to resistance of tumor cells to treatment with cisplatin, 5-FU and docetaxol. Interestingly, it has been shown that La stimulates internal ribosomal entry site (IRES)-dependent translation of XIAP and thereby stimulates its expression. Based on our preliminary data, we hypothesize that overexpression of La in oral cancer cells stimulates IRES-dependent XIAP translation and contributes to chemotherapy resistance. To test our hypothesis, we will ?in Specific Aim 1 ?demonstrate that La-dependent XIAP translation contributes to protection against cisplatin-induced apoptosis in SCC cells. Therefore we will determine, whether La-depleted SCC cells express less XIAP and are more sensitive to cisplatin-induced apoptosis. We also will analyze, whether La regulates the IRES-element of XIAP in SCC cells, by testing the IRESXIAP-luciferase reporter in cells harbouring reduced or elevated La levels. To determine whether the protein expression of La and XIAP positively correlate in vivo, we will apply immunohistochemistry and laser capture microdissection (LCM) on oral tumor tissue. Once completed, this aim will establish the underlying molecular mechanism of La-dependent XIAP expression in oral SCC. Since the combination treatment with cisplatin, 5-FU and docetaxel is considered the standard regime for chemotherapy in unresectable head and neck SCC, we will ?in Specific Aim 2 ?elucidate, whether La-dependent stimulation of XIAP expression dictates the response to combination treatment with cisplatin, 5-FU and docetaxel in SCC cells. Once completed, this aim may identify La as biomarker for resistance to chemotherapy in oral cancer. This project will focus on the underlying mechanism of La-dependent XIAP-mRNA translation contributing to chemotherapy resistance in oral SCC. This knowledge will foster our future research on identification of novel molecular decoys to specifically inhibit the interaction of the La protein and XIAP mRNAs to reduce XIAP expression and improve the survival rate and response to chemotherapy of oral cavity cancer patients.
Showing the most recent 10 out of 136 publications
