Publication Date

7-31-2013

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Supervisory Committee Chair

Cheryl L. Jorcyk

Supervisory Committee Member

Julia T. Oxford

Supervisory Committee Member

Ken Cornell

Abstract

Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine shown to be important in inflammation, hematopoiesis, development and bone homeostasis. Despite its role as a growth suppressor for many cancers, including breast cancer, OSM is currently being studied for its ability to promote tumor invasion and metastasis. Cathepsin D (CTSD) is a lysosomal protease found to be overexpressed and hypersecreted in breast and other cancers. In this study, we found OSM to induce the expression of CTSD protein in human breast cancer cells via the STAT3 and JNK2 pathways. Next, we investigated mechanisms resulting in the increased secretion of CTSD from tumor cells. Previous reports have shown that acidic extracellular pH and cellular transformation stimulate lysosomal trafficking, increase secretion of lysosomal proteases, and increase invasion. In this study, we observed that OSM induced a change in cellular morphology and that CTSD-containing lysosomes traffic to the newly formed cellular protrusions. The trafficking and secretion of CTSD was dependent on Na+/H+ exchanger (NHE) activity and OSM activation of the PI3K and p38 MAPK pathways. OSM induced the secretion of physiologically active CTSD which correlated with lysosomal location. Knockdown of CTSD also prevented an increase in invasive potential, even in the presence of OSM. Together, these results suggest that the expression of CTSD and location of CTSD-containing lysosomes are important aspects of the increase in invasive potential of tumor cells induced by OSM. This study provides further evidence that OSM may be an important therapeutic target for in the early stages of breast cancer metastasis.

Download

Share

COinS