- Collection:
- Atlanta University and Clark Atlanta University Theses and Dissertations
- Title:
- Expression of TGFB isoforms and their effects on migratory and invasive behavior of prostate cancer cells: involvement of PI3-KINASE/AKT Signaling pathway, 2012
- Creator:
- Walker, Lindsey Danielle
- Date of Original:
- 2010/2019
- Subject:
- Degrees, Academic
Dissertations, Academic - Location:
- United States, Georgia, Fulton County, Atlanta, 33.749, -84.38798
- Medium:
- theses
dissertations - Type:
- Text
- Format:
- application/pdf
- Description:
- Transforming growth factor-? (TGF?) is a secreted protein that is involved in the regulation of many cellular processes and has been implicated as a factor in cancer cell invasion and metastasis. Studies have indicated that different TGF? isoforms may exert differential effects on cancer cells during different stages of the disease, however very little is known about the expression patterns of the 3 isoforms in prostate cancer. Non traditional signaling pathways including P13-kinase have been associated with TGF?- mediated effects on cancer cell invasion and metastasis. Whether or not TGF? isoforms play a differential role in migration and invasion of prostate cancer, and act through P13 - Kinase, has not been investigated. In the present study, we have carried out expression analysis of TGF? isoforms and signaling components in cell line models representing different stages of prostate cancer and studied the differential effects of specific isoforms on migratory, invasive behavior and induction of the P13-Kinase and MAP-Kinase/ERK pathways. TGF?1 and TGF?3 were expressed in all prostate cell lines, with TGF?3 increasing in metastatic DU145, PC3 and PC3M cell lines. TGFI31 and TGFI33 induced motility and invasive behavior in PC3 cells, with TGF?3 being more potent in inducing invasive behavior. TGF?3 caused a significant increase in the phosphorylation of AKT (pAKT^473), a downstream target of P13-Kinase, in PC3 cells. LY294002, a P13-kinase inhibitor, blocked this induced migration and phosphorylation of AKT. Inhibitors of TGF?RI (SB43 1524) and Smad3 (SIS3) blocked TGF? isoform induced motility and TGF? isoform induced pAKT^473. There was no differential isoform effect on the phosphorylation of ERK (pERK). PD98059, a MEK inhibitor of MAP-Kinase/ERK, did inhibit TGF? isoform induced migration and pERK, but did not affect isoform induced pAK^T473. Furthermore, TGF? isoforms phosphorylate both Smad2 and Smad3 in a similar manner in PC3 cells. Based on these results, we conclude that TGF?3 is expressed in metastatic prostate cancer cell lines and is involved in induction of invasive behavior in these cells. Furthermore, these effects of TGF?3 are mediated via the P13- Kinase pathway and are TGF?RI and Smad3 dependent.
Date of award: 12/1/2012
Degree type: dissertation
Degree name: Doctor of Philosophy (PhD)
Granting institution: Clark Atlanta University
Department: School of Arts and Sciences, Biology
Advisor: Chaudhary, Jaideep
Advisor: Hinton, Cimona
Advisor: Odero-Marah, Valerie - Metadata URL:
- http://hdl.handle.net/20.500.12322/cau.td:2012_walker_lindsey_d
- Holding Institution:
- Atlanta University Center Robert W. Woodruff Library
- Rights:
-
