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Z. Zhang



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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-002 - Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2 (ID 190)

      09:30 - 09:30  |  Author(s): Z. Zhang

      • Abstract

      Background
      Lung cancer is the leading cause of cancer-related mortality worldwide and there are more than one million new cases reported worldwide each year. Small cell lung cancer (SCLC) makes up 15% to 20% of all lung cancers with a 5-year survival rate of 5% to 10%. Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of SCLC and contributes to both malignant transformation and therapeutic resistance. The emergence of BH3 mimetics that modulate Bcl-2 pathway by occupying the BH3 groove represents a rational approach for the treatment of this neoplasm. S1 is a BH3 mimetic that depends on Bax/Bak completely. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to S1 and the mechanism underlying the resistance of BH3 mimetics.

      Methods
      Western bolt was used to evaluate the contribution of Bcl-2 family members to the cellular response of 11 SCLC cell lines to a BH3 mimetic S1. Viable cells were determined using MTS assay. To study the potential mechanism of resistance to S1, we derived resistant lines from initially sensitive H1688 cells. Quantitative PCR was performed to investigate Bcl-2 up-regulation. Gene silencing and MEK/ERK inhibitor PD98059 were used to demonstrate the involvement of ERK1/2 signaling in S1-induced Bcl-2 expression.

      Results
      Results showed relatively higher levels of Bcl-2 and phosphorylated Bcl-2 (pBcl-2) characterized naïve SCLC cell lines that were de novo resistant to S1. Likewise, a progressive increase in the relative levels of Bcl-2 and pBcl-2 characterized the increased acquired resistance of H1688 cells following chronic exposure to S1. Furthermore, acute treatment of S1 induced Bcl-2 expression and phosphorylation. We showed that BH3 mimetics including S1 and ABT-737 induced ER stress and then activated MEK/ERK pathway. The dual function of MEK/ERK pathway in defining BH3 mimetics was illustrated: ERK1/2 activation leaded to Bcl-2 transcriptionally up-regulation and sustain phosphorylation in naïve 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 a positive feedback to promote ERK1/2 activation.Figure 1

      Conclusion
      These results provide significant novel insights into the molecular mechanisms for crosstalk between ER stress and endogenous apoptotic pathways in SCLC following BH3 mimetics treatment.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-002 - Resistance to BH3 mimetic S1 in non-small cell lung cancer cells that phosphorylate Bim through ERK1/2 and lead to its proteasomal degradation (ID 683)

      09:30 - 09:30  |  Author(s): Z. Zhang

      • Abstract

      Background
      Lung cancer is the leading cause of all cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type, accounting for 75–80% of all lung cancers. Bcl-2 is a central regulator of cell survival that is overexpressed in NSCLC and contributes to both malignant transformation and therapeutic resistance. We previously identified a small-molecule BH3 mimetic named S1 that exhibits nanomolar affinity towards Mcl-1, Bcl-2 and Bcl-XL. The purpose of this work was to study the key factors that determine the sensitivity of NSCLC cells to S1 and the mechanism underlying the resistance of this drug.

      Methods
      Acquired resistant cells were derived from initially sensitive NCI-H1975 cells. Western blot and co-immunoprecipitation were used to evaluate the contribution of Bcl-2 family members to the cellular response of several NSCLC cell lines to S1. Quantitative PCR and gene silencing were performed to investigate Bim down-regulation. PD98059 and MG-132 was used to inhibit the degradation of Bim.

      Results
      S1 can disrupt Bcl-2/Bim, Mcl-1/Bim and Bcl-XL/Bim complexes regardless of the levels of the anti-apoptotic proteins NSCLC cell lines. A progressive decrease in the relative levels of Bim characterized the increased de novo and acquired resistance of NSCLC cell lines. Furthermore, in resistant cells, acute treatment of S1 induced Bim phosphorylation on serine 69 and degradation via the proteasome pathway. ERK inhibitor PD98059 abrogated Bim phosphorylation and degradation and induced caspase activation and apoptosis. We showed that BH3 mimetics including S1 and ABT-737 induced ER stress and then activated MEK/ERK pathway in NSCLC cells. The function of MEK/ERK pathway in defining BH3 mimetics was illustrated: Bim was released from anti-apoptotic proteins by S1, ERK1/2 activation leaded to Bim sustained phosphorylation and then degraded by proteasome in naïve and acquired resistant NSCLC cells.Figure 1

      Conclusion
      We describe here a new mechanism for the regulation of Bim expression by phosphorylation protects NSCLC cells from BH3 mimetics induced apoptosis. These results provide significant novel insights into the molecular mechanisms for ERK1/2 mediated the crosstalk between the Bim regulation and ER stress to define BH3 mimetics in NSCLC cells.