Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620.
Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5-fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15weeks (~100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133(+) CD44(-) phenotype, and further exhibited loss of membrane-bound E-cadherin together with predominant nuclear β-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133(+) cells). These resistance phenomena, in turn, accentuate the malignant phenotype.
Tentes
I K
IK
Department of Biochemistry, Medical School, Democritus University of Thrace, 6th km Alexandroupolis-Komotini (Dragana), 68100 Alexandroupolis, Greece. itentes@med.duth.gr
Schmidt
W M
WM
Krupitza
G
G
Steger
G G
GG
Mikulits
W
W
Kortsaris
A
A
Mader
R M
RM
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism
D000071916:AC133 Antigen; D015703:Antigens, CD; D015820:Cadherins; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C000606023:PROM1 protein, human; D010455:Peptides; D051176:beta Catenin; D001374:Azacitidine; D005472:Fluorouracil