Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines

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Abstract
Resistance to anticancer drugs is a major obstacle preventing effective treatment of disseminated cancers. Understanding the molecular basis to chemoresistance is likely to provide better treatment. Cell lines resistant to cisplatin or 5‐fluorouracil (5‐FU) were established from human gastric carcinoma cell lines SNU‐638 and SNU‐620. Comparative proteomics involving 2‐dimensional gel electrophoresis (2‐DE) and matrix‐associated laser desorption ionization‐mass spectroscopy (MALDI‐MS) was performed on protein extracts from these parental and drug‐resistant derivative lines to screen drug resistance‐related proteins. Pyruvate kinase M2 (PK‐M2) was identified as a protein showing lower expression in cisplatin‐resistant cells compared to parental cells. Consistent with this finding, PK‐M2 activity was also lower in cisplatin‐resistant cells. Suppression of PK‐M2 expression by antisense oligonucleotide resulted in acquired cisplatin resistance in SNU‐638 cells. Furthermore, PK‐M2 activity in 11 individual human gastric carcinoma cell lines positively correlated with cisplatin sensitivity. Taken together, PK‐M2 protein and activity levels were lower in cisplatin‐resistant human gastric carcinoma cell lines compared to their parental cell lines. Furthermore, suppression of PK‐M2 expression using antisense oligonucleotides increased cisplatin resistance. These data clearly link PK‐M2 and cisplatin resistance mechanisms.