Role of Phosphatidylinositol 3-Kinase (Pi3K) in Protein Kinase C (Pkc)-Induced Breast Cancer Cell Metastasis

Alaa Qurban

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological and Environmental Sciences

Date of Award

Fall 2014

Abstract

Over 90% of the breast cancer related deaths are caused by metastasis. Epithelial to mesenchymal transition (EMT) is a prerequisite for metastasis. Macropinosomes are membrane ruffles that formed by actin-dependent endocytosis of fluids. Phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) are commonly deregulated in metastatic cells and are suggested to play a critical role in EMT and macropinosomes formation. However, molecular mechanisms of PI3K in PKC-induced metastasis, EMT and macropinosomes remain unclear. Recent studies suggested a role for PI3K and PKC in macropinosome formation, EMT, and cell migration. Based upon these results, we hypothesized that PI3K is indispensable for PKC-induced breast cancer cell metastasis. This hypothesis was tested with the following specific aims. Aim 1 tested the postulate that PI3K is required for PKC-induced breast cancer cell migration and invasion. In agreement with this hypothesis, inhibition of PI3K with wortmannin, a specific inhibition of PI3K, reversed Phorbol 12-myristate 13-acetate (PMA), an activator of PKC -induced breast cancer cell migration and invasion of breast cancer cells. Aim 2 evaluated the role of PI3K in PKC-induced EMT by testing the hypothesis that PKC-induced epithelial to mesenchymal transition is dependent upon PI3K activity. Inhibition of PI3K with wortmannin markedly reduced the expression of vinculin, a marker for EMT both in non-migratory cells and PMA-induced cells with higher migratory rate. Aim 3 assessed the role of PI3K in PKC-induced macropinosome formation. Compared to untreated control, PMA markedly increased the uptake of dextran indicating enhanced formation of macropinosome whereas wortmannin inhibited the uptake of dextran in control as well as PMA treated cells. In summary, our study identified that PI3K is upstream of PKC and is indispensable for eliciting PKC mediated breast cancer cell migration and invasion. Therefore, inhibition of PI3K may prevent or inhibit breast cancer metastasis and may result in better prognosis.

Advisor

Venugopalan Cheriyath

Subject Categories

Biology | Life Sciences

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