| Popis: |
The insulin receptor (IR) exists as two isoforms IR-A and IR-B, due to alternative splicing of exon 11. It is reported that IR-A is over-expressed in a number of cancers. This PhD aimed to assess the ratio of IR isoforms in prostate cancer cell lines and to manipulate the IR isoform ratio in an attempt to investigate the function of each isoform. I successfully manipulated IR isoforms by using siRNA to silence the IR-B isoform, exposing cells to different levels of glucose, IGFs, insulin or an insulin-sensitizing drug called metformin. I discovered the IR-B ratio was up-regulated under hyperglycaemic conditions, while in hypoglycaemic conditions, the IR-A ratio was up-regulated. In prostate cancer patients IR-A isoform was up-regulated in cancer regions compared to benign regions. This study also supports the theory that the IR-A isoform has a higher affinity for IGF-II and is involved in prostate cancer progression. Androgen receptor (AR) alterative splicing is involved in the development of prostate cancer resistance to androgen deprivation therapy. This study also assessed changes in AR alternative splicing in prostate cancer cell lines and cancer patient samples. And data suggest that the AR was over expressed in hyperglycaemic conditions in cell lines, and the study in prostate cancer patient samples suggest that AR variant 7 (AR-V7) is associated with cancer progression. This finding could have imp0l1ant implication to therapeutic strategies III prostate cancer patients presenting with diabetes. |
