| THE
IMPORTANCE OF INTERLEUKIN 8 IN CONFERRING CHEMO-RESISTANCE IN
PROSTATE CANCER: IMPLICATIONS FOR RESPONSE TO CONVENTIONAL CHEMOTHERAPY
AGENTS.
Dr David Waugh Queen's University Belfast |
Prostate cancer is poorly responsive to many chemotherapy regimens. Currently, the combination of Taxotere with Prednisilone is the only regimen shown to have a positive yet small survival benefit in patients with androgen-independent metastatic prostate cancer. The absence of response to chemotherapy suggests that prostate cancer cells acquire gene expression changes that render them resistant to the apoptosis-inducing effects of chemotherapy drugs. In understanding the proteins that confer this resistance to therapy, the scientific and clinical community will be better able to develop novel strategies to make chemotherapy more effective in prostate cancer.
Research in our laboratory has focused on determining the role of a specific signalling protein interleukin-8 in prostate cancer. Examining prostate biopsy tissue, we have determined that the levels of interleukin-8 expression are increased in prostate cancer cells over normal prostate epithelial cells. In addition, we have shown that prostate cancer cells also increase the expression of two proteins termed receptors on the cancer cell surface which recognise the interleukin-8 stimulus and thus enable the cell to respond to interleukin-8. Our analysis also shows that the increased expression of both interleukin-8 and interleukin-8 receptors is first detectable in the earliest stages of disease but is highest in androgen-independent prostate cancer. Our studies therefore suggest that prostate cancer cells are subject to a continuous stimulation by this protein that reaches a maximal strength in more advanced stages of the disease. The objective of our study funded by the Prostate Research Campaign was to determine the significance of interleukin-8 signalling in promoting the resistance of prostate cancer cells to chemotherapy.
In the first instance, we have shown that treatment with several chemotherapy drugs results in further increases in the expression of interleukin-8 and interleukin-8 receptors in prostate cancer cells. Subsequently, we have shown that as a direct response to interleukin-8 signalling, the expression of several proteins that are known to prevent cell death by a process termed “apoptosis” is increased in prostate cancer cells. The functional importance of interleukin-8 signalling in influencing the response of prostate cancer cells to chemotherapy was demonstrated when we were able to observe that chemotherapy drugs were much more effective in killing prostate cancer cells when interleukin-8 signalling was inhibited. Therefore, our data suggests that the re-inforcement of interleukin-8 signalling following exposure to chemotherapy drugs constitutes a novel mode of resistance that enables malignant prostate cancer cells to adapt to and evade the cell killing effect of chemotherapy drugs. Consequently, our future research will aim to validate strategies by which we can apply this knowledge in a therapeutic context with the objective of developing new strategies to increase the sensitivity of prostate cancer cells to chemotherapy agents.
Research summary dated 15 June 2005
Project 2003/03