Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines.
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.
Yoo
Byong Chul
BC
Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
Ku
Ja-Lok
JL
Hong
Sung-Hye
SH
Shin
Young-Kyoung
YK
Park
So Yeon
SY
Kim
Hark Kyun
HK
Park
Jae-Gahb
JG
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D015180:Electrophoresis, Gel, Two-Dimensional; D005472:Fluorouracil / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D011770:Pyruvate Kinase; D002945:Cisplatin; D005472:Fluorouracil