Mechanism of tumor metastases suppression by Drg1

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DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer among men in the United States, exceeding lung cancer by a narrow margin. Once prostate cancer is diagnosed, the most critical question is whether the disease is localized or it has already metastasized to other parts of the body. Unfortunately, none of the current medical technologies "cure" the metastatic disease, and the patients who have acquired metastatic prostate cancer have dismal chance of survival. Therefore, there is an urgent need for developing a novel approach of target-specific therapy to metastatic tumor cells, which requires more comprehensive understanding of the molecular mechanism of metastases. We have recently found that Drg1 acts as a tumor metastases suppressor in prostate cancer. Ample evidence from both clinical data and the results of in vitro as well as animal experiments overwhelmingly support the notion that Drg1 is a metastasis suppressor gene and that the down-regulation of the gene results in acceleration of tumor metastasis. The most crucial question is how Drg1 suppresses the tumor metastases. Our key discoveries in investigating this question are four folds: (i) interacts with Wnt receptor, LRP6, (ii) activates Wnt suppressor, GSK3(3, (iii) suppresses Akt activity, (iv) down-modulates the expression of the metastases promoter, ATF3, and (v) up-regulates the expression of the metastases suppressor gene KAI1 through ATF3 down-regulation. Therefore, we propose to test our hypothesis that Drg1 interacts with LRP6 leading to activation of GSK30 by tyrosine phosphorylation and also de-phosphorylates Akt which together results in blockade of the Wnt pathway (Hypothesis 1), and that this inactivation of the Wnt pathway suppresses the expression of the metastases promoting gene, ATF3, followed by down regulation of KAI1 (Hypothesis 2). Specific aim 1 is designed to test whether Drg-1 suppresses tumor cell invasion by blocking the Wnt pathway via interaction with LRP6 and following GSK3? activation in vitro. The purpose of the Specific aim 2 is to clarify how the interaction between Drg1 and LRP6 leads to metastasis suppression in animal models. In Specific aim 3, we will examine the status of expression of the Wnt signal molecules and Drg1 in clinical specimens from prostate cancer patients. The objective of Specific aim 4 is to examine whether Drg1 controls the KAI1 expression via Wnt pathway in vitro and in vivo. Our long-term goal is to elucidate the molecular mechanism of suppressor function of the Drg-1 gene in tumor progression and also to establish diagnostic/prognostic value of the Drg-1 pathway for prostate cancer. We believe that the results of the proposed experiments will provide fundamental information to accomplish our ultimate goal, the control of tumor metastasis in cancer patients.