The role of SSeCKS/AKAP12 in regulating chemotaxis and metastasis
Ko, Hyun Kyung
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Metastasis, especially prostate cancer metastasis is a leading cause of death for men in the US. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. Cell migration is necessary for a multistep process of metastasis, allowing tumor cells to disseminate. Chemotaxis, directional cell migration toward environmental cues, is believed to be crucial for successful metastasis, specifically for tumor cell dissemination. SSeCKS/AKAP12 encodes tumor- and metastasis-suppressing activity through its ability to scaffold oncogenic signaling mediators in a spatiotemporal manner. SSeCKS re-expression in cancer cells suppresses in vitro specific parameters of oncogenic growth, invasiveness and cell motility through scaffolding protein kinase C(PKC), F-actin, cyclins, Src. Moreover, In-vivo tumor model, SSeCKS re-expression inhibits metastatic tumor growth by suppressing vascular endothelial growth factor expression. Previous data indicated that the loss of SSeCKS or Rb correlates with prostate cancer (CaP) progression and that their deletion results in increased prostatic hyperplasia. Studies from our group demonstrated recently that SSeCKS-null ( Akap12 -/- ) mouse embryo fibroblasts (KO-MEF) suffer from an Rb-dependent premature senescence, and that the hyperplastic prostates in KO mice exhibit markers of increased senescence. Thus, this thesis focuses on two studies, which are the role of SSeCKS in regulating chemotaxis in cell-based systems and the role SSeCKS loss plays in promoting prostate cancer progression in the context of Rb gene deletion in a transgenic mouse model. Here, I demonstrate that SSeCKS attenuates chemotaxis by controlling cellular dynamics at the leading chemotactic edge through the scaffolding of phospholipids and signal mediators such as Rho family GTPase, GEF, and Src. In vivo studies show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy. Strikingly, the majority of mice with PIN lesions exhibit metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal and luminal epithelial cells. This work implies that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells. Taken together, these studies demonstrate that SSeCKS can serve as a critical metastatic suppressor, by suppressing chemotaxis and Rb loss-mediated malignancy mechanisms.