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Transcriptional upregulation of c-MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma.
Mol Oncol. 2018 12; 12(12):2191-2208.MO

Abstract

AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c-MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c-MYC markedly sensitizes AXL-dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c-MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c-MYC expression through activation of the AKT/β-catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin-resistant tumors with overexpression of AXL and activation of c-MYC.

Authors+Show Affiliations

Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30353671

Citation

Hong, Jun, et al. "Transcriptional Upregulation of c-MYC By AXL Confers Epirubicin Resistance in Esophageal Adenocarcinoma." Molecular Oncology, vol. 12, no. 12, 2018, pp. 2191-2208.
Hong J, Maacha S, Belkhiri A. Transcriptional upregulation of c-MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma. Mol Oncol. 2018;12(12):2191-2208.
Hong, J., Maacha, S., & Belkhiri, A. (2018). Transcriptional upregulation of c-MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma. Molecular Oncology, 12(12), 2191-2208. https://doi.org/10.1002/1878-0261.12395
Hong J, Maacha S, Belkhiri A. Transcriptional Upregulation of c-MYC By AXL Confers Epirubicin Resistance in Esophageal Adenocarcinoma. Mol Oncol. 2018;12(12):2191-2208. PubMed PMID: 30353671.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcriptional upregulation of c-MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma. AU - Hong,Jun, AU - Maacha,Selma, AU - Belkhiri,Abbes, Y1 - 2018/11/05/ PY - 2018/06/12/received PY - 2018/09/19/revised PY - 2018/10/10/accepted PY - 2018/10/26/pubmed PY - 2019/8/24/medline PY - 2018/10/25/entrez KW - AXL KW - R428 KW - c-MYC KW - epirubicin KW - esophageal adenocarcinoma KW - β-catenin SP - 2191 EP - 2208 JF - Molecular oncology JO - Mol Oncol VL - 12 IS - 12 N2 - AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c-MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c-MYC markedly sensitizes AXL-dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c-MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c-MYC expression through activation of the AKT/β-catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin-resistant tumors with overexpression of AXL and activation of c-MYC. SN - 1878-0261 UR - https://www.unboundmedicine.com/medline/citation/30353671/Transcriptional_upregulation_of_c_MYC_by_AXL_confers_epirubicin_resistance_in_esophageal_adenocarcinoma_ L2 - https://doi.org/10.1002/1878-0261.12395 DB - PRIME DP - Unbound Medicine ER -