Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells.
5-Fluorouracil (5-FU) is commonly used to treat human colon cancers but resistance to this compound is frequently observed in clinics. To characterize mechanisms of resistance to 5-FU and to develop new strategies for overcoming it, we established two cell lines that were resistant to 5-FU but not other chemotherapeutic agents from parental 5-FU-sensitive cell lines. Western blot analysis revealed that these resistant cells overexpressed the proteins Bcl-XL, Bcl-Xs, and Bik, and further data showed that the cells were resistant to 5-FU-induced DNA damage and cell cycle disorder. However, in parental cells, enforced expression of Bcl-XL protein provided only limited protection from 5-FU-induced apoptosis and overexpression of Bcl-XL protein did not affect 5-FU-induced DNA damage or cell cycle changes; these findings suggested that overexpression of Bcl-XL protein was not the major contributor to 5-FU resistance in any of our cells lines. Even so, knockdown of Bcl-XL protein expression by Bcl-XL-specific small interfering RNA could inhibit proliferation more effectively in 5-FU-resistant cells than in 5-FU-sensitive cells, and the combination of Bcl-XL-specific small interfering RNA and 5-FU had additive effect on the inhibition of 5-FU-resistant cells. These results suggest that down-regulation of Bcl-XL protein expression might provide a new treatment strategy for human 5-FU-resistant colon cancer therapy.
Zhu
Hongbo
H
Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Guo
Wei
W
Zhang
Lidong
L
Davis
John J
JJ
Teraishi
Fuminori
F
Wu
Shuhong
S
Cao
Xiaobo
X
Daniel
Jonathan
J
Smythe
W Roy
WR
Fang
Bingliang
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D016196:S Phase; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D008156:Luciferases; D005472:Fluorouracil