Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism

Qiong Liu, Chris T. Harvey, Hao Geng, Changhui Xue, Vivian Chen, Tomasz M. Beer, David Z. Qian

    Research output: Contribution to journalArticle

    26 Scopus citations

    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. Conclusion: 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.

    Original languageEnglish (US)
    Pages (from-to)1028-1037
    Number of pages10
    JournalProstate
    Volume73
    Issue number10
    DOIs
    StatePublished - Jul 2013

    Keywords

    • JNK
    • MDH2
    • chemotherapy response
    • docetaxel
    • metabolism

    ASJC Scopus subject areas

    • Oncology
    • Urology

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