Author ORCID Identifier

https://orcid.org/0000-0002-8699-8996

Date Available

6-1-2018

Year of Publication

2017

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Advisor

Dr. Rolf J. Craven

Abstract

The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor (EGFR) in cancer cells, and we reviewed multiple signaling-associated pathways that are important in trafficking wild-type and mutant EGFR. To better understand the potential of PGRMC1 in receptor tyrosine kinase trafficking, we extended our research to the insulin receptor (IR). Changes in insulin signaling have been linked to multiple diseases, because IR plays a key role in glucose metabolism, cellular survival and proliferation. We found PGRMC1 to co-precipitate with IR in cancer cells and in an adipose model system. PGRMC1 increased IR plasma membrane levels in multiple cancer cell lines, and was also found to increase plasma membrane levels of two glucose transporters. Treatment with a PGRMC1 ligand significantly increased IR levels in human adipocytes. Moreover, we demonstrate that both insulin binding and glucose uptake are dependent on PGRMC1.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.446

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