Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling


Docetaxel chemotherapy improves symptoms and survival in men with metastatic hormone-refractory prostate cancer (HRPC). However, about 50% of patients do not respond to Docetaxel but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of Docetaxel-resistance in HRPC. We used iTRAQ-mass spectrometry analysis to identify key proteins involved in the development of Docetaxel resistance using Docetaxel sensitive PC3 cells and Docetaxel-resistant PC3 cell line (PC3-Rx) developed by Docetaxel dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Serum/plasma levels of the targets in patient samples were measured by ELISA. The IC50 for Docetaxel in the PC3-Rx cells was 13-fold greater than the parent PC-3 cell line (p=0.004). Protein profiling identified MIC-1 and AGR2 as respectively up- and down regulated in Docetaxel resistant cells. PC-3 cells treated with recombinant MIC-1 also became resistant to Docetaxel (p=0.03). Conversely, treating PC3-Rx cells with MIC1- siRNA restored sensitivity to Docetaxel (p=0.02). Knockdown of AGR2 expression in PC3 cells resulted in Docetaxel resistance (p=0.007). Furthermore, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy was associated with progression of the cancer (p=0.006) and shorter survival after treatment (p=0.002). Overall, these results suggest that both AGR2 and MIC-1 play a role in Docetaxel resistance in HRPC. In addition, a rise in serum/plasma MIC-1 level after cycle one of Docetaxel may be an indication to abandon further treatment. Further investigation of MIC-1 as a biomarker and therapeutic target for Docetaxel-resistance HRPC is clearly warranted.

Type Journal
Authors Zhao, L.; Lee, B.Y.; Brown, D.A.; Molloy, M.P.; Marx, G.M.; Pavlakis, N.; Boyer, M.J.; Stockler, M.; Kaplan, W.; Breit, S.N.; Sutherland, R.L.; Henshall, S.M.; Horvath, L.G.
Published Date 2009-10-01
Published Volume 69
Published Issue 19
Published Pages 7696-7703
Status Published in-print
DOI 10.1158/0008-5472.CAN-08-4901
URL link to publisher's version
OpenAccess link to author's accepted manuscript version