title: Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
authors: Qiong
authors: Q
authors: Liu
authors: Chris T
authors: CT
authors: Harvey
authors: Hao
authors: H
authors: Geng
authors: Changhui
authors: C
authors: Xue
authors: Vivian
authors: V
authors: Chen
authors: Tomasz M
authors: TM
authors: Beer
authors: David Z
authors: DZ
authors: Qian
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D000077143:Docetaxel; D004351:Drug Resistance / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010101:Oxygen Consumption / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D043823:Taxoids; D000077143:Docetaxel; D008291:Malate Dehydrogenase
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