Research Team
PI: Farrokh Asadi, Rush CON
CO-PI: Barbara Swanson, Rush CON
CO-PI: Subhash Kukreja, Department of Medicine, Section of Endocrinology, University of Illinois at Chicago
Award Period
04/01/2015 - 10/30/2016
Funding Source
College of Nursing Research Fund for Faculty Pilot Grants
Abstract
During early stages of prostate cancer, tumor cells are dependent on androgen as a growth factor and withdrawal of androgen results in apoptotic cell death and clinical remissions. However, tumor recurrences after therapeutic interventions are commonly associated with increasing androgen independence of the tumor cells and increasing resistance to pro-apoptotic and chemotherapeutic agents1. Overexpression of IL-6 and PTHrP have been implicated in prostate cancer progression and bone metastases2,3. Serum IL-6 and PTHrP levels are elevated in patients with untreated metastatic prostate cancer and correlates with poor prognosis and chemoresistance4,5. The interactions between prostate tumor cells and bone marrow derived
mesenchymal stem cells (BM-MSCs) have also been shown to be critical in the development of androgenindependency and bone metastases6-9. Previously, we have reported that the expression of PTHrP is enhanced in prostate cancer and is greater in poorly differentiated carcinoma as compared with the welldifferentiated tumors10. We have also reported that the expression of PTHrP may contribute to the apoptosisresistant phenotype in prostate cancer cells11, and repression of PTHrP expression increases the caspase-3 activation and sensitivity of androgen-independent prostate cancer cell line to apoptosis11. In our preliminary studies we have shown that IL-6 and PTHrP mRNA and protein are highly expressed in androgen-independent prostate cancer cells, and co-culture of androgen-independent prostate cancer cells with BM-MSCs leads to further increase of IL-6 and PTHrP expression. In addition, we have demonstrated that exposure to exogenous IL-6 or PTHrP stimulates the growth of androgen-independent cells, whereas it induces growth arrest in androgen-dependent cell line. These findings provide indirect evidence for the importance of IL-6 and PTHrP in mediating the progression of prostate tumor and its transformation to an androgen-independent phenotype. Recently, has been shown that IL-6 induces the expression of PTHrP in human osteoblastic cells12, however, no studies have directly tested the IL-6 mediated PTHrP expression in prostate cancer progression.
Hypothesis
We hypothesize that: 1) IL-6 induction of PTHrP is crucial in tumor progression and androgenindependent growth of prostate cancer; 2) IL-6 inhibitors will repress PTHrP expression and provoke apoptosis in androgen-independent prostate cancer cells.