Dissertation
CHARACTERIZATION OF ROLES OF THE LYSOPHOSPHATIDIC ACID-CCN1 SIGNALING AXIS IN HUMAN PROSTATE CANCER CELLS
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2024
DOI:
https://doi.org/10.7273/000006496
Abstract
Cysteine rich angiogenic factor (CCN1/Cyr61) and connective tissue growth factor (CCN2/CTGF) are members of the CCN family of matricellular proteins. These secreted proteins interact with extracellular matrix proteins and integrins to modulate cell signaling. CCN proteins have been implicated in survival and mitogenic responses in various cancers. CCN1 and CCN2 are the two early inducible genes in this family. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lipid growth factors known to contribute to tumor progression in prostate cancer. In previous work, our group showed that LPA stimulates proliferation and migration in prostate cancer cells via the G protein-coupled receptor (GPCR), LPA receptor 1 (LPAR1). We also demonstrated that CCN1 expression is induced by LPA in human prostate cancer cells. However, the roles of CCN1 and CCN2 in LPA signaling were not elucidated. In this project, the involvement of CCNs were examined in more detail, using the PC-3 human prostate cancer cell line as a model system. The results show that both LPA and S1P up-regulate CCN1 and CCN2 between 2-4 hours. These inductions occur after the acute phase of LPA-stimulated extracellular signal-related kinase (Erk) activation, but before a later phase of Erk activation. Structure-activity studies of physiologic LPA species showed that, in PC-3 cells, only 18:1-LPA and not 18:0-LPA activates Erk and induces CCN1. LPA enhances cell-substrate adhesion after 2 hours, and this response (as well as basal adhesion) are reduced after siRNA-mediated knockdown of CCN1. A global proteomics analysis revealed that LPA increases the levels of additional proteins involved in extracellular matrix interactions after 2 hours, including metastasis-related in colon cancer-1 (MACC1). The effects of LPA on the levels of MACC1 and several other adhesion-related proteins were suppressed following CCN1 knockdown. Taken together, these data establish a role for CCN1 in LPA-induced cell-substrate adhesion, and in the effects of LPA on the expression levels of multiple adhesion-related proteins and pathways. Thus, CCN1 contributes to a later phase of signal transduction following the acute phase of LPAR1-mediated events. CCN1 and other matricellular proteins that are regulated by LPA represent potential therapeutic targets in prostate cancer.
Metrics
4 File views/ downloads
28 Record Views
Details
- Title
- CHARACTERIZATION OF ROLES OF THE LYSOPHOSPHATIDIC ACID-CCN1 SIGNALING AXIS IN HUMAN PROSTATE CANCER CELLS
- Creators
- Pravita Balijepalli
- Contributors
- Kathryn E Meier (Chair)Salah-uddin Ahmed (Committee Member)Senthil Natesan (Committee Member)Christopher John Davis (Committee Member)Clifford Berkman (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Pharmacy and Pharmaceutical Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 197
- Identifiers
- 99901122440801842
- Language
- English
- Resource Type
- Dissertation