Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance

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Shin, Young-Kyoung; Yoo, Byong Chul; Chang, Hee Jin; Jeon, Eunkyung; Hong, Sung-Hye; Jung, Mi-Sun; Lim, Soo-Jeong; Park, Jae-Gahb
Issue Date
American Association for Cancer Research
Cancer Res. 2005 Apr 15;65(8):3162-70
Antimetabolites, Antineoplastic/*pharmacologyAurovertins/pharmacologyCell Line, TumorCell Proliferation/drug effectsColonic Neoplasms/*drug therapy/*enzymology/geneticsDown-RegulationDrug Resistance, NeoplasmEnergy MetabolismEnzyme Inhibitors/pharmacologyFluorouracil/*pharmacologyHumansMitochondria/*enzymologyMitochondrial Proton-Translocating ATPases/*antagonists &inhibitors/biosynthesis/geneticsOligomycins/pharmacologyRNA, Small Interfering/geneticsTransfection
5-Fluorouracil (5-FU) is widely used for treatment of advanced colorectal cancer. However, it is common for such patients to develop resistance to 5-FU, and this drug resistance becomes a critical problem for chemotherapy. The mechanisms underlying this resistance are largely unknown. To screen for proteins possibly responsible for 5-FU resistance, cells resistant to 5-FU were derived from human colon cancer cell lines and two-dimensional gel electrophoresis-based comparative proteomics was done. Two-dimensional gel electrophoresis data showed there was lower expression of the alpha subunit of mitochondrial F(1)F(0)-ATP synthase (ATP synthase) in 5-FU-resistant cells compared with parent cells. Western blotting showed that expression of other ATP synthase complex subunits was also lower in 5-FU-resistant cell lines and that these resistant cells also showed decreased ATP synthase activity and reduced intracellular ATP content. The ATP synthase inhibitor, oligomycin A, strongly antagonized 5-FU-induced suppression of cell proliferation. When 5-FU sensitivity was compared with ATP synthase activity in six different human colon cancer cell lines, a positive correlation has been found. Furthermore, suppressed ATP synthase d-subunit expression by siRNA transfection increased cell viability in the presence of 5-FU. Bioenergetic dysfunction of mitochondria has been reported as a hallmark of many types of cancers (i.e., down-regulation of ATP synthase beta-subunit expression in liver, kidney, colon, squamous oesophageal, and lung carcinomas, as well as in breast and gastric adenocarcinomas). Our findings show that ATP synthase down-regulation may not only be a bioenergetic signature of colorectal carcinomas but may also lead to cellular events responsible for 5-FU resistance.
0008-5472 (Print)
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College of Medicine/School of Medicine (의과대학/대학원)Surgery (외과학전공)Journal Papers (저널논문_외과학전공)
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