Indexed by:期刊论文
Date of Publication:2013-11-01
Journal:JOURNAL OF THORACIC ONCOLOGY
Included Journals:SCIE、PubMed、Scopus
Volume:8
Issue:7
Page Number:S767-S767
ISSN No.:1556-0864
Key Words:SCLC; ERK1/2; Bcl-2 phosphorylation; BH3 mimetics
Abstract:BACKGROUND AND PURPOSE
B cell lymphoma 2 (Bcl-2) is a central regulator of cell survival that is overexpressed in the majority of small-cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to Bcl-2 homology domain-3 (BH3) mimetic S1 and the mechanism underlying the resistance of BH3 mimetics.
EXPERIMENTAL APPROACHES
Western blot was used to evaluate the contribution of Bcl-2 family members to the cellular response of SCLC cell lines to S1. Acquired resistant cells were derived from initially sensitive H1688 cells. Quantitative PCR and gene silencing were performed to investigate Bcl-2 up-regulation.
KEY RESULTS
A progressive increase in the relative levels of Bcl-2 and phosphorylated Bcl-2 (pBcl-2) characterized the increased de novo and acquired resistance of SCLC cell lines. Furthermore, acute treatment of S1 induced Bcl-2 expression and phosphorylation. We showed that BH3 mimetics, including S1 and ABT-737, induced endoplasmic reticulum (ER) stress and then activated MAPK/ERK pathway. The dual function of MAPK/ERK pathway in defining BH3 mimetics was illustrated; ERK1/2 activation leaded to Bcl-2 transcriptional up-regulation and sustained phosphorylation in naive and acquired resistant SCLC cells. pBcl-2 played a key role in creating resistance of S1 and ABT-737 not only by sequestrating pro-apoptotic proteins, but also sequestrating a positive feedback to promote ERK1/2 activation.
CONCLUSIONS AND IMPLICATIONS
These results provide significant novel insights into the molecular mechanisms for crosstalk between ER stress and endogenously apoptotic pathways in SCLC following BH3 mimetics treatment.
Professor
Supervisor of Doctorate Candidates
Supervisor of Master's Candidates
Title : 智能生物制造教育部重点实验室
Gender:Male
Alma Mater:大连理工大学
Degree:Doctoral Degree
School/Department:化工海洋与生命学院
Discipline:Biochemistry and Molecular Biolog. Biochemical Engineering. Chemical Biology
Business Address:大连理工大学 智能生物制造教育部重点实验室 生命科学与药学系
Contact Information:liuyubo@dlut.edu.cn
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