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

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

doi:10.3892/or.2019.7171

July-2019 Volume 42 Issue 1

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July-2019 Volume 42 Issue 1

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Article

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

Authors:
- 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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Affiliations: Department of Urology, Aichi Medical University School of Medicine, Nagakute 480‑1195, Japan, Division of Research Support, Research Creation Support Center, Aichi Medical University, Nagakute 480‑1195, Japan, Division of Research Creation, Research Creation Support Center, Aichi Medical University, Nagakute 480‑1195, Japan
Pages: 224-230
|
Published online on: May 24, 2019

https://doi.org/10.3892/or.2019.7171
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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.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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