title: RNA interference-mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin-induced apoptosis dependent on JNK activation.
abstract: In the present study, we downregulated FANCF expression by small interfering RNA (siRNA) in OVCAR ovarian cancer cells to address the effects of decreased FANCF expression on the function of the Fanconi anemia (FA)/breast cancer susceptibility gene (BRCA) pathway. Furthermore, we investigated whether this method increases the sensitivity of OVCAR3 cells to adriamycin (ADM) and the possible mechanism(s). We found that silencing of FANCF inactivated the FA/BRCA pathway by decreasing the monoubiquitination and focus formation of FANCD2 and reduced the function of the FA/BRCA pathway, resulting in the inhibition of cell proliferation, increased cell apoptosis and DNA damage in OVCAR3 cells. Moreover, we observed that silencing of FANCF enhanced the antiproliferative effect of ADM in OVCAR3 cells and increased ADM intracellular accumulation consequently sensitizing OVCAR3 cells to ADM. Furthermore, silencing of FANCF increased cell apoptosis of OVCAR3 cells which was caused by decreased mitochondrial membrane potential (MMP)-induced DNA damage, activated Jun N-terminal kinase (JNK), increased release of cytochrome c, increased expression of cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP) dependent on JNK activation following treatment of ADM. Collectively, we confirm that silencing of FANCF sensitizes OVCAR3 ovarian cancer cells to ADM, suggesting that FANCF may serve as a potential target for therapeutic strategies in the treatment of ovarian cancer.
authors: Department of Pharmacology, China Medical University, Heping, Shenyang, Liaoning 110001, PR China.
authors: Miao
authors: M
authors: He
authors: Hai-Gang
authors: HG
authors: Sun
authors: Jun-Ying
authors: JY
authors: Hao
authors: Yan-Lin
authors: YL
authors: Li
authors: Jian-Kun
authors: JK
authors: Yu
authors: Yuan-Yuan
authors: YY
authors: Yan
authors: Lin
authors: L
authors: Zhao
authors: Na
authors: N
authors: Li
authors: Yan
authors: Y
authors: Wang
authors: Xue-Feng
authors: XF
authors: Bai
authors: Zhao-Jin
authors: ZJ
authors: Yu
authors: Zhi-Hong
authors: ZH
authors: Zheng
authors: Xiao-Yi
authors: XY
authors: Mi
authors: En-Hua
authors: EH
authors: Wang
authors: Min-Jie
authors: MJ
authors: Wei
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052219:Fanconi Anemia Complementation Group F Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; D034741:RNA, Small Interfering; D004317:Doxorubicin; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3