Journal Article

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

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

2019

Overview

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.

• Publisher: D.A. Spandidos,Spandidos Publications,Spandidos Publications UK Ltd
• Subject: Antineoplastic agents / Apoptosis / Cancer cells / Cancer research / Cancer therapies / castration-resistant prostate cancer / Cell cycle / Cell Cycle - drug effects / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Chemotherapy / Cytotoxicity / Dehydrogenases / Docetaxel / Docetaxel - pharmacology / Down-Regulation / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Synergism / Enzyme Inhibitors - pharmacology / Enzymes / Flow cytometry / Gene Expression Regulation, Neoplastic / Humans / L-Lactate Dehydrogenase - antagonists & inhibitors / lactate dehydrogenase-A / lactate dehydrogenase-A inhibitor / Male / Medical prognosis / Metabolism / Metastasis / Oxamic Acid - pharmacology / Penicillin / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - enzymology / sodium oxamate / Studies / Tumors