title: Silencing of fused toes homolog enhances cisplatin sensitivity in cervical cancer cells by inhibiting epidermal growth factor receptor-mediated repair of DNA damage.
abstract: Overexpression of epidermal growth factor receptor (EGFR) is related to chemo-/radioresistance and poor prognosis in many cancers. EGFR is activated by cisplatin, and this may lead to resistance to this drug. Fused toes homolog (FTS) is an E2 variant that lacks the active cysteine residue required for ubiquitin transfer. Previously, we reported that FTS interacts with EGFR and activates DNA-dependent protein kinase (DNA-PK) upon irradiation. Here, we investigated the role of FTS in cisplatin sensitivity in ME180 cervical cancer cells.
  
  
  
  Protein expression was assessed using western blot analyses in four cervical cell lines (ME180, CaSki, HeLa, and SiHa). FTS was silenced using a siRNA-based approach. Interactions between proteins were assessed by immunoprecipitation. Immunofluorescence was used to visualize DNA double-strand breaks and the expression of phospho-DNA-PK.
  
  
  
  Among the lines tested, ME180 cells showed the highest basal expression of EGFR and increased nuclear phosphorylated EGFR in response to cisplatin. In ME180 cells, the activation of EGFR and DNA-PK by cisplatin was attenuated by silencing FTS. FTS-silencing augmented cisplatin-induced cell death and cisplatin-induced DNA damage assessed by γH2AX. Immunoprecipitation showed binding of FTS with EGFR and DNA-PK.
  
  
  
  FTS is involved in EGFR-mediated repair of DNA damage induced by cisplatin in ME180 cells. This suggests that FTS can be a target to increase the efficacy of cisplatin in cervical cancer cells that exhibit increased nuclear phosphorylated EGFR in response to cisplatin.
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Chungdae-ro 1, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea.
authors.forename: Prabakaran D
authors.initials: PD
authors.lastname: Subramanian
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Chungdae-ro 1, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea.
authors.forename: Zhengzhe
authors.initials: Z
authors.lastname: An
authors.affiliation: Department of Environmental and Tropical Medicine, Konkuk University College of Medicine, Chungju, Chungbuk, 27478, Republic of Korea.
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Chungbuk National University College of Medicine, Chungdae-ro 1, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea. wynpark@chungbuk.ac.kr.
authors.forename: Woo-Yoon
authors.initials: WY
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D020868:Gene Silencing; D006657:Histones / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D034741:RNA, Small Interfering / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: C486377:AKTIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin
keywords: Cisplatin; DNA repair; Epidermal growth factor receptor; Fused toes homolog