The authors disclose no potential conflicts of interest.
Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism†
Article first published online: 6 FEB 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 73, Issue 10, pages 1028–1037, July 2013
How to Cite
Liu, Q., Harvey, C. T., Geng, H., Xue, C., Chen, V., Beer, T. M. and Qian, D. Z. (2013), Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism. Prostate, 73: 1028–1037. doi: 10.1002/pros.22650
- Issue published online: 30 MAY 2013
- Article first published online: 6 FEB 2013
- Manuscript Accepted: 10 JAN 2013
- Manuscript Received: 12 NOV 2012
- Department of Defense Prostate Cancer Research Program. Grant Number: W81XWH-10-1-0142
- PNW Prostate Cancer SPORE Pilot Award
- National Cancer Institute (Public Health Service grants). Grant Numbers: R01CA119125, R01CA149253
- chemotherapy response;
Resistance to chemotherapy represents a significant obstacle in prostate cancer therapeutics. Novel mechanistic understandings in cancer cell chemotherapeutic sensitivity and resistance can optimize treatment and improve patient outcome. Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown.
In a bed-side to bench-side reverse translational approach, we used cDNA microarray and qRT-PCR to identify genes that are associated with biochemical relapse after chemotherapy. Further, we tested the function of these genes in cell proliferation, metabolism, and chemosensitivity in prostate cancer cell lines.
We report that the gene encoding mitochondrial malate dehydrogenase 2 (MDH2) is overexpressed in clinical prostate cancer specimens. Patients with MDH2 overexpression had a significantly shorter period of relapse-free survival (RFS) after undergoing neoadjuvant chemotherapy. To understand the molecular mechanism underlying this clinical observation, we observed that MDH2 expression was elevated in prostate cancer cell lines compared to benign prostate epithelial cells. Stable knockdown of MDH2 via shRNA in prostate cancer cell lines decreased cell proliferation and increased docetaxel sensitivity. Further, MDH2 shRNA enhanced docetaxel-induced activations of JNK signaling and induced metabolic inefficiency.
Taken together, these data suggest a novel function for MDH2 in prostate cancer development and chemotherapy resistance, in which MDH2 regulates chemotherapy-induced signal transduction and oxidative metabolism. Prostate 73: 1028–1037, 2013. © 2013 Wiley Periodicals, Inc.