Targeting lactate dehydrogenase-A promotes docetaxel-induced cytotoxicity predominantly in castration-resistant prostate cancer cells

Hiroyuki Muramatsu, Makoto Sumitomo, Shingo Morinaga, Keishi Kajikawa, Ikuo Kobayashi, Genya Nishikawa, Yoshiharu Kato, Masahito Watanabe, Kenji Zennami, Kent Kanao, Kogenta Nakamura, Susumu Suzuki, Kazuhiro Yoshikawa

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Abstract

Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castration-resistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDH-A, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDH-A in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castration-providing strains PC3, DU145, LNCaP and LN-CSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDH-A inhibitor. Changes in the expression level of LDH-A were analyzed by western blotting. Cell growth and survival were evaluated with a WST-1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDH-A expression. Synergistic cytotoxicity was observed by combining DOC and SO in LN-CSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC-3 and DU145 cells, caused cell cycle arrest in G2-M phase and increased the number of cells in the sub-G1 phase of cell cycle in LN-CSS cells. SO promoted DOC induced apoptosis in LN-CSS cells, which was partially caused by the inhibition of DOC-induced increase in LDH-A expression. The results strongly indicated that LDH-A serves an important role in DOC resistance in advanced PC cells and inhibition of LDH-A expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.

Original languageEnglish
Pages (from-to)224-230
Number of pages7
JournalOncology reports
Volume42
Issue number1
DOIs
Publication statusPublished - 07-2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Muramatsu, H., Sumitomo, M., Morinaga, S., Kajikawa, K., Kobayashi, I., Nishikawa, G., Kato, Y., Watanabe, M., Zennami, K., Kanao, K., Nakamura, K., Suzuki, S., & Yoshikawa, K. (2019). Targeting lactate dehydrogenase-A promotes docetaxel-induced cytotoxicity predominantly in castration-resistant prostate cancer cells. Oncology reports, 42(1), 224-230. https://doi.org/10.3892/or.2019.7171