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Resistance to BH 3 mimetic S 1 in SCLC cells that up‐regulate and phosphorylate B cl‐2 through ERK 1/2
Author(s) -
Liu Yubo,
Zhang Zhichao,
Song Ting,
Liang Furong,
Xie Mingzhou,
Sheng Hongkun
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12243
Subject(s) - mapk/erk pathway , phosphorylation , gene silencing , p38 mitogen activated protein kinases , microbiology and biotechnology , cell culture , chemistry , cell growth , biology , cancer research , biochemistry , gene , genetics
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 ( BH 3) mimetic S 1 and the mechanism underlying the resistance of BH 3 mimetics. Experimental Approaches Western blot was used to evaluate the contribution of B cl‐2 family members to the cellular response of SCLC cell lines to S 1 . Acquired resistant cells were derived from initially sensitive H 1688 cells. Quantitative PCR and gene silencing were performed to investigate B cl‐2 up‐regulation. Key Results A progressive increase in the relative levels of B cl‐2 and phosphorylated B cl‐2 ( pBcl ‐2) characterized the increased de novo and acquired resistance of SCLC cell lines. Furthermore, acute treatment of S 1 induced B cl‐2 expression and phosphorylation. We showed that BH 3 mimetics, including S 1 and ABT ‐737, induced endoplasmic reticulum ( ER ) stress and then activated MAPK / ERK pathway. The dual function of MAPK / ERK pathway in defining BH 3 mimetics was illustrated; ERK 1/2 activation leaded to B cl‐2 transcriptional up‐regulation and sustained phosphorylation in naïve and acquired resistant SCLC cells. pBcl ‐2 played a key role in creating resistance of S 1 and ABT ‐737 not only by sequestrating pro‐apoptotic proteins, but also sequestrating a positive feedback to promote ERK 1/2 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 BH 3 mimetics treatment.