Role of G1P3 in Breast Cancer Metastases

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological and Environmental Sciences

Date of Award

Spring 2015

Abstract

Tumor metastasis is one of the leading causes of cancer related deaths among women in the United States. While several mechanisms contribute to breast cancer metastases, cell death survival is known to confer the metastatic potential. Recently, G1P3 has been reported to antagonize apoptosis in hyperplasia. Hence, based on its survival activity, we hypothesize that G1P3 might play a role in developing metastasis. Preliminary studies showed faster migration rate in MCF-7 breast cancer cell line with G1P3 overexpression (p < 0.05, 1.6 fold). In addition, results from transwell invasion assays affirmed that G1P3 overexpressing cells invaded two times more than vector control cells suggesting a pivotal role of G1P3 in developing metastases. Cytoskeleton remodeling is a crucial step for cancer cells to metastasize. In agreement with its ability to augment the migration of cancer cells, G1P3 overexpression resulted in actin polymerization. Additionally, the accumulation of actin filaments, like F-actin arcs, increased formation of migratory structures such as lamellopodia, filopodia, and actin bundles which observed in G1P3 expressing cells.vBased on the localization of G1P3 into mitochondria, measurement of mitochondrial ROS (MtROS) identified a significant increase in ROS levels in G1P3 expressing cells compared to the control. Further investigation on the role of G1P3-induced MtROS migration and cytoskeletal organization was identified by suppressing ROS with N-acetyl cysteine (NAC) which markedly decreased the migration rate and F-actin levels in G1P3 overexpressing cells. Since increased levels of ROS are suggested to activate protein kinase C (PKC) to induce actin polymerization, the role of PKC in mediating the effects of G1P3 on cell migratory structures and cell migration was tested. Inhibition of PKC with a small molecule inhibitor (BIM 1) blocked the migration of G1P3 expressing cells in wound healing assays (2.22 fold, p ??? 0.0001). Taken together, our results suggest that G1P3 induced ROS play a critical role in actin cytoskeletal remodeling via PKC activation to confer metastatic potential. Therefore, inhibiting mitochondrial functions of G1P3 may be beneficial in preventing breast cancer metastasis, the major cause of over 90% of breast cancer related deaths.

Advisor

Venugopalan Cheriyath

Subject Categories

Biology | Life Sciences

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