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API5 induces cisplatin resistance through FGFR signaling in human cancer cells

Authors
 Han Sol Jang  ;  Seon Rang Woo  ;  Kwon-Ho Song  ;  Hanbyoul Cho  ;  Doo Byung Chay  ;  Soon-Oh Hong  ;  Hyo-Jung Lee  ;  Se Jin Oh  ;  Joon-Yong Chung  ;  Jae-Hoon Kim  ;  Tae Woo Kim 
Citation
 Experimental and Molecular Medicine, Vol.49(9) : e374, 2017 
Journal Title
 Experimental and Molecular Medicine 
ISSN
 1226-3613 
Issue Date
2017
MeSH
Animals ; Antineoplastic Agents/pharmacology* ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/genetics* ; Apoptosis Regulatory Proteins/metabolism* ; Bcl-2-Like Protein 11/metabolism ; Cell Line, Tumor ; Chemoradiotherapy ; Cisplatin/pharmacology* ; Disease Models, Animal ; Drug Resistance, Neoplasm/genetics* ; Female ; Humans ; MAP Kinase Signaling System/drug effects ; Mice ; Nuclear Proteins/genetics* ; Nuclear Proteins/metabolism* ; RNA, Small Interfering ; Receptor, Fibroblast Growth Factor, Type 1/metabolism ; Receptors, Fibroblast Growth Factor/metabolism* ; Signal Transduction/drug effects* Tumor Burden Uterine Cervical Neoplasms/genetics Uterine Cervical Neoplasms/metabolism Uterine Cervical Neoplasms/pathology Uterine Cervical Neoplasms/therapy Xenograft Model Antitumor Assays
Abstract
Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5high cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/160921
DOI
10.1038/emm.2017.130
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실)
Yonsei Authors
김재훈(Kim, Jae Hoon)
조한별(Cho, Han Byoul)
채두병(Chay, Doo Byung)
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