title: Knockdown of focal adhesion kinase reverses colon carcinoma multicellular resistance.
abstract: Chemotherapy resistance in solid tumors is broad and encompasses diverse unrelated drugs. Three-dimensional multicellular spheroids (MCSs) are a good model for studying in vitro drug resistance. In the current study, we investigated the role of focal adhesion kinase (FAK) in 5-fluorouracil (5-FU) chemoresistance in colon carcinoma MCS culture cells. The expression of FAK was inhibited significantly by specific small hairpin RNA targeting FAK. The suppression of FAK expression did not affect the growth of spheroid cells. However, silencing of FAK combined with 5-FU treatment significantly decreased the 50% inhibitory concentration (IC(50)) of 5-FU and markedly increased the population of apoptosis cells, which was associated with the reduction of the levels of Akt and nuclear factor-kappa B (NF-kappaB). Moreover, knockdown of FAK could inhibit tumor growth and increase the sensitivity of the tumor to 5-FU in the nude mouse xenograft. These results indicate that while not affecting cellular proliferation in the absence of 5-FU, RNA interference targeting FAK potentiated 5-FU-induced cytotoxicity in vitro and in vivo, and partially reversed multicellular resistance, which may contribute to its chemosensitizing effect through efficiently suppressing Akt/NF-kappaB activity.
authors.affiliation: Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Chen
authors.forename: Zhan-Xiang
authors.initials: ZX
authors.lastname: Wang
authors.forename: Ping-An
authors.initials: PA
authors.lastname: Chang
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Zhi-Heng
authors.initials: ZH
authors.lastname: Bian
authors.forename: Lan
authors.initials: L
authors.lastname: Zou
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: He
authors.forename: Hou-Jie
authors.initials: HJ
authors.lastname: Liang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil