Variable NF-κB pathway responses in colon cancer cells treated with chemotherapeutic drugs

BMC Cancer

Temesgen Samuel¹  Khalda Fadlalla¹  Dominique N Gales¹  Balananda DK Putcha²  Upender Manne² 

[1] School of Veterinary Medicine, Pathobiology Department and TU Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA

[2] Department of Pathology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

关键词: Chemokine;    Cytokine;    Drug response;    Camptothecin;    NF-κB;    Colon cancer;   

Others  :  1125190
DOI  :  10.1186/1471-2407-14-599

 received in 2014-04-01, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

Background

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is activated in cells exposed to various stimuli, including those originating on the cell surface or in the nucleus. Activated NF-κB signaling is thought to enhance cell survival in response to these stimuli, which include chemotherapy and radiation. In the present effort, we determined which anticancer drugs preferentially activate NF-κB in colon cancer cells.

Methods

NF-κB reporter cells were established and treated with 5-fluorouracil (5-FU, DNA/RNA damaging), oxaliplatin (DNA damaging), camptothecin (CTP, topoisomerase inhibitor), phleomycin (radiomimetic), or erlotinib (EGFR inhibitor). The activation of NF-κB was assessed by immunofluorescence for p65 translocation, luciferase assays, and downstream targets of NF-κB activation (cIAP2, and Bcl-X_L) were evaluated by immunoblotting, by ELISA (CXCL8 and IL-6 in culture supernatants), or by gene expression analysis.

Results

Colon cancer cells responded variably to different classes of therapeutic agents, and these agents initiated variable responses among different cell types. CPT activated NF-κB in SW480 colon cancer cells in a dose-dependent manner, but not in HCT116 cells that were either wild-type or deficient for p53. In SW480 colon cancer cells, NF-κB activation by CPT was accompanied by secretion of the cytokine CXCL8, but not by up-regulation of the anti-apoptotic genes, cIAP2 or Bcl-X_L. On the contrary, treatment of HCT116 cells with CPT resulted in up-regulation of CXCR2, a receptor for CXCL8, without an increase in cytokine levels. In SW480 cells, NF-κB reporter activity, but not cytokine secretion, was inhibited by SM-7368, an NF-κB inhibitor.

Conclusion

The results show that, in response to cancer therapeutic agents, NF-κB activation varies with the cellular make up and that drug-induced NF-κB activation may be functionally uncoupled from anti-apoptotic outcomes found for other stimuli. Some cancer cells in a heterogeneous tumor tissue may, under therapeutic pressure, release soluble factors that have paracrine activity on neighboring cells that express the cognate receptors.

【 授权许可】

   
2014 Samuel et al.; licensee BioMed Central Ltd.

【 图 表 】

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