Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance.

Abstract

5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75 kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC.

• Authors: Young-Kyoung Shin, Byong Chul Yoo, Yong Sang Hong, Hee Jin Chang, Kyung Hae Jung, Seung-Yong Jeong, Jae-Gahb Park
• Journal: Electrophoresis (Electrophoresis) Vol. 30 Issue 12 Pg. 2182-92 (Jun 2009) ISSN: 1522-2683 [Electronic] Germany
• PMID: 19582719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neoplasm Proteins
• Proteome
• Irinotecan
• Pyruvate Kinase
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, enzymology, metabolism)
• Down-Regulation
• Drug Resistance, Neoplasm
• Female
• Fluorouracil (administration & dosage, pharmacology)
• Glycolysis (drug effects)
• Humans
• Irinotecan
• Leucovorin (administration & dosage)
• Male
• Middle Aged
• Neoplasm Proteins (biosynthesis, metabolism)
• Proteome (metabolism)
• Pyruvate Kinase (metabolism)
• Reproducibility of Results
• Up-Regulation (drug effects)