Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo.

Xiqian Han,Shu Zhang,Fengshan Wang,Xiaobing Zhang,Yikang Shi,Hui Li,Shengshi Huang

doi:10.18632/oncotarget.5334

Abstract

Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab.

Highlights

IntroductionHER2 ( named as ErbB2) is a member of the EGFR receptor tyrosine kinase (RTK) family, which include EGFR, HER3, and HER4
HER2 is a member of the EGFR receptor tyrosine kinase (RTK) family, which include EGFR, HER3, and HER4
In order to investigate whether tunicamycin inhibit growth against tumor cell lines as the same manner as in normal cell lines, Sulforhodamine B (SRB) assay was performed in several breast cancer cell lines as well as in some normal cell lines such as MCF-10A, HL7702, HEK293T, HMLE and HUVEC

Summary

Introduction

HER2 ( named as ErbB2) is a member of the EGFR receptor tyrosine kinase (RTK) family, which include EGFR, HER3, and HER4. HER2 is activated by the formation of homodimers or heterodimers with other EGFR receptors. HER2 is generally regarded as the preferred heterodimerization partner for each of the ligand-bound EGFR receptors [1]. Two key signaling pathways activated by the EGFR family dimers are the MAPK pathway, which stimulates proliferation, and the PI3K/Akt pathway, which promotes tumour cell survival. The PI3K/Akt pathway is the predominant oncogenic pathway downstream of HER2 [2]. HER2 plays important roles in cell growth, survival, and differentiation in a complex manner. HER2 is overexpressed in 25–30% of human breast cancers and its overexpression is associated with more aggressive disease behavior and poor response to chemotherapy [3,4,5]

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Results

Conclusion