Date of Award

8-11-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Susanna F. Greer

Second Advisor

Charlie Garnett-Benson

Third Advisor

Timothy L. Denning

Abstract

Chemotherapy and radiation therapy remain the backbone of cancer treatments, and now cancer immunotherapy offers promising new approaches for the treatment of malignancies. One of the major obstacles for chemo-based therapies is acquired chemoresistance. We find Regulator of G-protein signaling protein (RGS10) is an important regulator of cell survival and chemoresistance in ovarian cancer. Our findings further indicate RGS10 transcript expression is suppressed by DNA hypermethylation and histone deacetylation during acquired chemoresistance in ovarian cancer. We identify two important epigenetic regulators, HDAC1 and DNMT1, which exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Inhibition of DNMT1 or HDAC1 significantly increases RGS10 expression and cisplatin-mediated cell death.

We further focus on modulation of death receptors in advanced colorectal cancer (CRC) cells. We use a combination treatment of irradiation and proteasome inhibition to further induce activation of tumor-specific immune responses. We investigate the effect of the 26S proteasome inhibitor bortezomib alone or in combination with radiotherapy, on the expression of death receptors in normal colon and in colorectal cancer cell lines. Our results indicate a combination of 26S proteasome inhibition and sub-lethal radiation significantly increases the sensitivity of carcinoma cells to apoptosis. Combination treatment up-regulates cell surface expression of DR4, DR5 and Fas by increasing their transcriptional activation. Thus, the combination treatment enhanced sensitivity to killing through FAS and TRAIL receptors by CD8+ T cells. We further characterized the mechanisms by which radiation controls CRC expression of death receptors. We have shown that sub-lethal irradiation increases expression of our target molecules by enhancing histone acetylation at promoter regions through decreasing binding of HDAC2 and HDAC3, and by DNA hypomethylation, via decreasing binding of DNMT1. In sum, our studies provide insight into the alteration of molecular pathways involved in cancer cell death and survival.

Share

COinS