Development of an Anti-Cancer Approach Through a Novel Pathway of Translational Regulation

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ABSTRACT STAT3 (Signal Transducer and Activator of Transcription 3) is a transcriptional regulator that plays crucial role in malignant transformation of the cells, tumor growth and metastasis. STAT3 activity or expression is upregulated in 70% of human tumors contributing to a rapid cancer progression and therefore it is a potential pharmacological target in cancer treatments. It was demonstrated that STAT3 knockdown reduced abnormal cell growth. However, direct and indirect inhibitors of STAT3 activity did not provide expected efficacy, demanding search for alternative strategies for STAT3 inhibition. The presence of STAT3 aberrant expression in different types of tumors and potential ability to treat cancer through decrease of STAT3 expression determines high significance of the study. The central idea of the current project is based on control of STAT3 expression during its synthesis on the ribosome through modulation of components of the novel pathway recently discovered by us. The RAPP (Regulation of Aberrant Protein Production) pathway specifically regulates protein synthesis, degrading mRNAs of the proteins that do not properly interact during their synthesis on the ribosome. Our hypothesis is that the RAPP translational regulators may be used to control STAT3 expression and therefore restrict cell proliferation and tumor growth. The concept of this type of STAT3 regulation was never explored before, little is known about STAT3 translational partners and about their modulation to control STAT3 expression, thus demonstrating novelty of the project. Our preliminary data demonstrate that the RAPP pathway is involved in regulation of STAT3. The following specific aims are designed for this project: (1) identify novel STAT3 translational partners during its synthesis on the ribosome, and (2) test the hypothesis that RAPP translational regulators can be modulated to decrease STAT3 expression and cancer cell proliferation. The study is based on unique technologies for detection and identification of proteins during translation by site-specific photo-crosslinking and iPINCH approaches. We will use candidate and unbiased approaches to test RAPP regulators in STAT3 control. The experiments will also involve cell culture models and RNA interference techniques or overproduction to verify involvement of the RAPP components in STAT3 regulation. In this project we will determine potential anti-cancer properties of the RAPP modulation by measuring cancer cell proliferation and apoptosis. The success of the proposal will build a foundation for the future studies with animal models and use of chemical regulators (potential drugs) to develop new anti-cancer medicine. Potentially, this proposal will lead to development of conceptually new directions in pharmacological treatments of cancer.