Ruo-Xi Wang1,2, Xiao-En Xu1,2, Liang Huang1,2, Sheng Chen1,2, Zhi-Ming Shao1,2,3. 1. Department of Breast Surgery, Fudan University Shanghai Cancer Center/Cancer Institute, Shanghai 200032, China. 2. Department of Oncology, Shanghai Medical College, Shanghai 200032, China. 3. Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
Abstract
BACKGROUND: Triple-negative breast cancers (TNBCs) are initially responsive to chemotherapy, but most recurrent TNBCs develop resistance. Autophagy is believed to play dual roles in cancer and might contribute to chemoresistance. In this study, we aimed to investigate the role of autophagy and its regulator, eukaryotic elongation factor 2 kinase (eEF2K), in determining the biological nature of TNBC. METHODS: We used in vitro models of TNBC, namely, paclitaxel-resistant cell lines derived from sensitive cell lines. Various approaches to measuring autophagy flux were applied. We assessed the effects of inhibiting autophagy and silencing eEF2K on cell viability, tumor formation and invasion. We also collected residual tumor samples from 222 breast cancer patients who underwent neoadjuvant chemotherapy and measured eEF2K and LC3 expression levels by immunohistochemistry (IHC). Multivariate survival analysis was used to determine prognostic variables. RESULTS: Compared to the parental lines, the chemoresistant lines exhibited enhanced starvation-stimulated autophagy and showed significant decreases in cell viability, growth and invasion upon treatment with autophagy inhibitors. eEF2K silencing also resulted in the suppression of autophagic activity and in aggressive biological behavior. In the survival analysis, residual tumor LC3 (P=0.001) and eEF2K (P=0.027) expression levels were independent prognostic factors for patients who underwent neoadjuvant chemotherapy, especially in those with TNBC. CONCLUSIONS: Our study indicated that eEF2K and autophagy play key roles in the maintenance of aggressive tumor behavior and chemoresistance in resistant TNBC. eEF2K silencing may be a novel strategy for the treatment of TNBC. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Triple-negative breast cancers (TNBCs) are initially responsive to chemotherapy, but most recurrent TNBCs develop resistance. Autophagy is believed to play dual roles in cancer and might contribute to chemoresistance. In this study, we aimed to investigate the role of autophagy and its regulator, eukaryotic elongation factor 2 kinase (eEF2K), in determining the biological nature of TNBC. METHODS: We used in vitro models of TNBC, namely, paclitaxel-resistant cell lines derived from sensitive cell lines. Various approaches to measuring autophagy flux were applied. We assessed the effects of inhibiting autophagy and silencing eEF2K on cell viability, tumor formation and invasion. We also collected residual tumor samples from 222 breast cancer patients who underwent neoadjuvant chemotherapy and measured eEF2K and LC3 expression levels by immunohistochemistry (IHC). Multivariate survival analysis was used to determine prognostic variables. RESULTS: Compared to the parental lines, the chemoresistant lines exhibited enhanced starvation-stimulated autophagy and showed significant decreases in cell viability, growth and invasion upon treatment with autophagy inhibitors. eEF2K silencing also resulted in the suppression of autophagic activity and in aggressive biological behavior. In the survival analysis, residual tumor LC3 (P=0.001) and eEF2K (P=0.027) expression levels were independent prognostic factors for patients who underwent neoadjuvant chemotherapy, especially in those with TNBC. CONCLUSIONS: Our study indicated that eEF2K and autophagy play key roles in the maintenance of aggressive tumor behavior and chemoresistance in resistant TNBC. eEF2K silencing may be a novel strategy for the treatment of TNBC. 2019 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Autophagy; chemo-resistant; eukaryotic elongation factor 2 kinase (eEF2K); neoadjuvant chemotherapy (NAC); triple-negative breast cancer (TNBC)
Authors: Ahmed A Ashour; Abdel-Aziz H Abdel-Aziz; Ahmed M Mansour; S Neslihan Alpay; Longfei Huo; Bulent Ozpolat Journal: Apoptosis Date: 2014-01 Impact factor: 4.677
Authors: Ayca Gucalp; Sara Tolaney; Steven J Isakoff; James N Ingle; Minetta C Liu; Lisa A Carey; Kimberly Blackwell; Hope Rugo; Lisle Nabell; Andres Forero; Vered Stearns; Ashley S Doane; Michael Danso; Mary Ellen Moynahan; Lamia F Momen; Joseph M Gonzalez; Arooj Akhtar; Dilip D Giri; Sujata Patil; Kimberly N Feigin; Clifford A Hudis; Tiffany A Traina Journal: Clin Cancer Res Date: 2013-08-21 Impact factor: 12.531
Authors: Ibrahim Tekedereli; S Neslihan Alpay; Clint D J Tavares; Zehra E Cobanoglu; Tamer S Kaoud; Ibrahim Sahin; Anil K Sood; Gabriel Lopez-Berestein; Kevin N Dalby; Bulent Ozpolat Journal: PLoS One Date: 2012-07-20 Impact factor: 3.240
Authors: Claire E J Moore; Xuemin Wang; Jianling Xie; Jo Pickford; John Barron; Sergio Regufe da Mota; Matthias Versele; Christopher G Proud Journal: Cell Signal Date: 2016-01-18 Impact factor: 4.315