Gene Silencing of FANCF Potentiates the Sensitivity to Mitoxantrone through Activation of JNK and p38 Signal Pathways in Breast Cancer Cells

Liu, Yanlin; Zhao, Lin; Sun, Hai-Gang; Yu, Jie-Ping; Li, Na; Liang, Jing-wei; He, Miao; Bai, Xuefeng; Yu, Zhaojin; Zheng, Zhaohui; Mi, Xiaoyi; Wang, Enhua

doi:10.1371/journal.pone.0044254

Cited by 23 publications

(25 citation statements)

References 53 publications

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“…This implies that p38 kinase activation may play an inhibitory role in FA/BRCA pathway activation. MAP kinases, JNK and p38, are activated when the FA/BRCA pathway is inhibited by gene silencing of FANCF in breast cancer cells [37]. A role for these kinases has been reported in hematopoiesis of FANCC-deficient cells [38].…”

Section: Discussionmentioning

confidence: 99%

Ouabain, a Cardiac Glycoside, Inhibits the Fanconi Anemia/BRCA Pathway Activated by DNA Interstrand Cross-Linking Agents

et al. 2013

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Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na+/K+-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members―digitoxin and digoxin―down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca2+ ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Ouabain, a Cardiac Glycoside, Inhibits the Fanconi Anemia/BRCA Pathway Activated by DNA Interstrand Cross-Linking Agents

et al. 2013

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“…Recent reports show that inhibition of the BRCA/FA pathway by siRNA (e.g. FANCF , BRCA1 , and BRCA2 ) is effective in treating breast and ovarian cancers . Inhibiting the BRCA/FA pathway and decreasing the CD24 + /44 + population in GEM‐resistant BTC cells could be a new treatment for BTC, although we need to consider the influence on somatic cells and the drug delivery system.…”

Section: Discussionmentioning

confidence: 99%

BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

et al. 2015

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The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24+/44+ population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24+/44+ population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24+/44+ population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24+/44+ population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24+/44+ population in BTC.

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“…For instances, PJ34 [46] , celastrol [47] , mTOR kinase inhibitor [48] , Nedd8 conjugation system inhibitor [49] , DDN [50] , phenylbutyrate [51] and monoketone analogs of curcumin [52] are all against FANCD2 monoubiquitination. Mitoxantrone can promotes the activity of USP11 [53] and inhibit FANCF [54] , and both also compromise FANCD2 monoubiquitination. Further, bortezomib can interfere with FA/BRCA1 focus formation [55] and thus sensitize tumor cells.…”

Section: Fa Pathway-targeted Agents In Cancer Therapymentioning

confidence: 99%

Advances in the Understanding of Fanconi Anemia Complementation Group D2 Protein (FANCD2) in Human Cancer

Shen

Zhang

2015

Can Cell Microenviron

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Fanconi anemia (FA) is a rare human genetic disease, resulting from dysfunction in any of 17 known complementation proteins: FANC-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q & S, and other unknowns. Besides the severe bone marrow failure, an extremely high incidence of cancer as well as many other clinic symptoms associated with FA patients, FA cells are known of insufficiency in homologous recombination, DNA mismatch repair, nucleotide excision repair, translesion DNA synthesis, and other molecular defects, leading to genome instability. Those similar molecular and cellular/tissue features show that all FA proteins function in one common signaling pathway, namely, the FA pathway. The monoubiquitination of FANCD2 is the central step of the FA pathway activation upon DNA damage or during DNA replication. The molecular functions of FANCD2 emerge as a very attractive filed of investigation in cancer research. Herein, we review the recent progresses in FANCD2 functions at these rapidly progressed aspects.

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Gene Silencing of FANCF Potentiates the Sensitivity to Mitoxantrone through Activation of JNK and p38 Signal Pathways in Breast Cancer Cells

Cited by 23 publications

References 53 publications

Ouabain, a Cardiac Glycoside, Inhibits the Fanconi Anemia/BRCA Pathway Activated by DNA Interstrand Cross-Linking Agents

Ouabain, a Cardiac Glycoside, Inhibits the Fanconi Anemia/BRCA Pathway Activated by DNA Interstrand Cross-Linking Agents

BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer

Advances in the Understanding of Fanconi Anemia Complementation Group D2 Protein (FANCD2) in Human Cancer

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