Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
Abstract Background Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while th...
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doaj-09a0088263ad4fa4a43290b1694a48b22021-01-17T12:57:14ZengBMCBMC Cancer1471-24072020-01-0120111210.1186/s12885-019-6480-9Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinomaXia Liao0Ge Song1Zihan Xu2Yang Bu3Fan Chang4Fengan Jia5Xuelian Xiao6Xuejiao Ren7Mei Zhang8Qingan Jia9Department of Nutrition, First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Nutrition, First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Burns and Plastic Surgery, Shaanxi Provincial People’s HospitalDepartment of Hepatobiliary Surgery, General Hospital, Ningxia Medical UniversityMetabolite Research Center, Shaanxi Institute of MicrobiologyMetabolite Research Center, Shaanxi Institute of MicrobiologyDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong UniversityMedical College of Yan’an UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. Results Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.https://doi.org/10.1186/s12885-019-6480-9Hepatocellular carcinomaOxaliplatin resistanceSaracatinibWnt signalingABCG1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xia Liao Ge Song Zihan Xu Yang Bu Fan Chang Fengan Jia Xuelian Xiao Xuejiao Ren Mei Zhang Qingan Jia |
spellingShingle |
Xia Liao Ge Song Zihan Xu Yang Bu Fan Chang Fengan Jia Xuelian Xiao Xuejiao Ren Mei Zhang Qingan Jia Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma BMC Cancer Hepatocellular carcinoma Oxaliplatin resistance Saracatinib Wnt signaling ABCG1 |
author_facet |
Xia Liao Ge Song Zihan Xu Yang Bu Fan Chang Fengan Jia Xuelian Xiao Xuejiao Ren Mei Zhang Qingan Jia |
author_sort |
Xia Liao |
title |
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma |
title_short |
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma |
title_full |
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma |
title_fullStr |
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma |
title_full_unstemmed |
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma |
title_sort |
oxaliplatin resistance is enhanced by saracatinib via upregulation wnt-abcg1 signaling in hepatocellular carcinoma |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2020-01-01 |
description |
Abstract Background Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. Results Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib. |
topic |
Hepatocellular carcinoma Oxaliplatin resistance Saracatinib Wnt signaling ABCG1 |
url |
https://doi.org/10.1186/s12885-019-6480-9 |
work_keys_str_mv |
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