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PBMC activation via the ERK and STAT signaling pathways enhances the anti-tumor activity of Staphylococcal enterotoxin A

Molecular and Cellular Biochemistry volume 434, pages 75–87 (2017)Cite this article

Abstract

Staphylococcal enterotoxin A (SEA) is well known as a superantigen and is highly potent in activating T lymphocytes. And it has been used clinically as an immunomodifier in the treatment of a number of tumors for years. However, the mechanism of its action remains largely unclear. In this study, SEA was found to significantly inhibit the proliferation and induce the death of human lung carcinoma A549 cells when co-cultured with human peripheral blood mononuclear cells (PBMCs). SEA could also induce the proliferation of human PBMCs and stimulate human PBMCs to release a wide range of cytokines that have broad anti-tumor activities such as IFN-γ, TNF-α, IL-2. Furthermore, SEA was found in PBMCs to induce a rapid and long-lasting phosphorylation of extracellular signal-regulated kinases (ERKs) which was significantly inhibited by MEK/ERK pathway inhibitors U0126 and PD0325901, and a late onset of phosphorylation of signal transducers and activators of transcription (STATs) which was significantly inhibited by a pan-JAK inhibitor Pyridone 6 (P6). Unexpectedly constitutive ERK or STATs phosphorylation was also significantly inhibited by P6 or U0126 in a dose-dependent manner, respectively. Summing up, our data reveal SEA may function as a novel protein drug used for cancer immunotherapy via inducing activation of PBMCs, immune cell crosstalk-dependent activation of ERK and STATs, and production of tumor-suppressive cytokines.

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Acknowledgements

We thank Lucinda Beck for her critical reading of the manuscript. This work was supported by the National Natural Science Foundation of China [Grant Numbers 81301948]; the Grow Seedlings Project of Department of Education of Guangdong Province [2013LYM0070]; and the Natural Science Foundation from Guangdong Science and Technology Department [Grant Number 2014A020212343].

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Affiliations

  1. The Second Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou, 510260, People’s Republic of China

    Xueting Liu, Liping Zeng, Yang Xie, Lanyan Xiao, Shan Wang, Junyan Zhang, Zehong Zou, Ying He, Ailin Tao & Jianguo Zhang

  2. Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Zhongqiu Zhao

  3. Barnes-Jewish Hospital, St. Louis, MO, 63110, USA

    Zhongqiu Zhao

  4. Guangdong Provincial Key Laboratory of Allergy & Immunology/Allergy Research Branch of the State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China

    Jianxing He

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  1. Xueting Liu
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  2. Liping Zeng
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Contributions

XL and AT conceived and designed the experiments; XL, YX, LX, and LZ performed the experiments; JZ, SW, JZ, and YH analyzed the data; HC and ZHZ contributed reagents/materials/analysis tools; XL, ZQZ, and AT wrote the manuscript.

Corresponding authors

Correspondence to Ailin Tao or Jianguo Zhang.

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The authors declare no conflict of interest.

Electronic supplementary material

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Supplementary material 1 Fig. S1. ELISA

analysis of cytokines and chemokines secretion by SEA-stimulated PBMCs in vitro. Fig. S2. Quantitation of mRNA expression of cytokines and chemokines production in SEA-stimulated PBMCs in vitro. Fig. S3. Quantitation of CNE2 cell growth after co-cultured with SEA pretreated PBMCs. Table S1. Primers used for real-time quantitative PCR. (DOC 1610 kb)

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Liu, X., Zeng, L., Zhao, Z. et al. PBMC activation via the ERK and STAT signaling pathways enhances the anti-tumor activity of Staphylococcal enterotoxin A. Mol Cell Biochem 434, 75–87 (2017). https://doi.org/10.1007/s11010-017-3038-5

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  • DOI: https://doi.org/10.1007/s11010-017-3038-5

Keywords

  • Staphylococcal enterotoxin A
  • Cancer immunotherapy
  • MEK/ERK pathway
  • STATs
  • PBMCs
  • Cytokines