title: Gene silencing of FANCF potentiates the sensitivity to mitoxantrone through activation of JNK and p38 signal pathways in breast cancer cells.
abstract: Fanconi anemia complementation group-F (FANCF) is a key factor to maintain the function of FA/BRCA, a DNA-damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. In this study, we examined the effects and mechanisms of FANCF-RNAi on the sensitivity of breast cancer cells to mitoxantrone (MX). FANCF silencing by FANCF-shRNA blocked functions of FA/BRCA pathway through inhibition of FANCD2 mono-ubiquitination in breast cancer cell lines MCF-7 and T-47D. In addition, FANCF shRNA inhibited cell proliferation, induced apoptosis, and chromosome fragmentation in both breast cancer cells. We also found that FANCF silencing potentiated the sensitivity to MX in breast cancer cells, accompanying with an increase in intracellular MX accumulation and a decrease in BCRP expression. Furthermore, we found that the blockade of FA/BRCA pathway by FANCF-RNAi activated p38 and JNK MAPK signal pathways in response to MX treatment. BCRP expression was restored by p38 inhibitor SB203580, but not by JNK inhibitor SP600125. FANCF silencing increased JNK and p38 mediated activation of p53 in MX-treated breast cancer cells, activated the mitochondrial apoptosis pathway. Our findings indicate that FANCF shRNA potentiates the sensitivity of breast cancer cells to MX, suggesting that FANCF may be a potential target for therapeutic strategies for the treatment of breast tumors.
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang City, Liaoning, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Haigang
authors.initials: H
authors.lastname: Sun
authors.forename: Jiankun
authors.initials: J
authors.lastname: Yu
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Jingwei
authors.initials: J
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Bai
authors.forename: Zhaojin
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Mi
authors.forename: Enhua
authors.initials: E
authors.lastname: Wang
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005199:Fanconi Anemia / Q000201:enzymology / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D052219:Fanconi Anemia Complementation Group F Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology* / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019313:BRCA1 Protein; C499905:FANCD2 protein, human; C499901:FANCF protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D052219:Fanconi Anemia Complementation Group F Protein; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D008942:Mitoxantrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases