Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Kenneth V. Honn

Abstract

Thromboxane A2 (TXA2) is a major arachidonic acid metabolite that signals through TXA2 receptors (TP) to induce platelet aggregation and smooth muscle contraction. TXA2 receptors are expressed as two different isoforms in humans, namely TP-alpha (TPα) and TP-beta (TPβ), which have common and distinct signaling pathways. Of the two TP receptor isoforms, studies have shown that TPα impacts tumor growth and progression of lung cancer. Previously our studies demonstrated that activation of Thromboxane receptor by TXA2 agonists could regulate prostate cancer (PCa) cell motility and cytoskeletal reorganization through activation of Rho-A. The primary objective of this study is to investigate the functional role of TPα in prostate cancer progression and metastasis.

Our data indicates that of the two TPR isoforms, human PCa cell lines only express TPα and that expression of TPα is higher in PCa cells compared to cultured normal prostate epithelial cells, such as RWPE1. Furthermore, expression of TPα was observed to be higher in clinical PCa specimens when compared with normal tissue, and expression was higher in tumor tissues with Gleason scores of 7 and above. In response to the TXA2 mimetic, IBOP, DU145 cells that have higher endogenous levels of TPα compared to other cell lines, up regulated expression of the growth factor Amphiregulin (AREG) and its receptor EGFR. Introduction of an expression plasmid encoding TPα into another PCa cell line, PC3 (PC3-TPα), led to a similar phenotype in response to IBOP, thereby confirming a link between TPα and over expression of AREG and EGFR.

Increase in AREG expression mediated by TPα seems to involve EGFR and AMP activated protein kinase (AMPK) signaling pathways. PC3-TPα cells treated with IBOP were also highly invasive compared to PC3-Neo cells; this invasiveness mediated by TPα was affected by pre treatment with an EGFR inhibitor. In a subcutaneous animal model, mice injected with PC3-TPα exhibited greater tumor growth and increased neo vascularization compared to mice with PC3-Neo cells. Also when mice was injected with PC3-TPα cells and Matrigel BME, increased angiogenesis was observed as indicated by the accumulation of blood compared to mice with PC3-Neo cells. Collectively these data suggest that activation of TPα receptor in PCa cells increases the level of growth factors such as AREG and its receptor EGFR that might be mediated through AMPK, thereby implicating TPα in prostate cancer progression.

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