A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines
Por:
Martinez-Balibrea, E, Plasencia, C, Gines, A, Martinez-Cardus, A, Musulen, E, Aguilera, R, Manzano, JL, Neamati, N and Abad, A
Publicada:
1 abr 2009
Resumen:
We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatin-resistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r = -0.846, P = 0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P = 0.026). High PK-M2 levels were associated with high p53 levels (P = 0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatin-treated colorectal cancer. [Mol Cancer Ther 2009;8(4): 771-8]
Filiaciones:
:
Hosp Univ Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Univ So Calif, Sch Med, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA
Plasencia, C:
Univ So Calif, Sch Med, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA
Gines, A:
Hosp Univ Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
:
Hosp Univ Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
:
Hosp Univ Germans Trias & Pujol, Dept Pathol, Barcelona 08916, Spain
Aguilera, R:
Univ So Calif, Sch Med, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA
:
Hosp Univ Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Neamati, N:
Univ So Calif, Sch Med, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA
Abad, A:
Hosp Univ Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
|