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Tanshinone IIA pretreatment promotes cell survival in human lung epithelial cells under hypoxia via AP-1-Nrf2 transcription factor

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Cell Stress and Chaperones Aims and scope

Abstract

Activator protein-1 (AP-1) plays a decisive role in cell proliferation, apoptosis, and inflammation under hypoxia; thus, AP-1 subunits or dimers could be modulated for a desired phenomenon in a cell using a suitable compound of therapeutic potential. Herein, we used Tanshinone-IIA as an AP-1 (subunits) modulator, and the purpose of the study was to investigate the signaling mechanism exhibited by Tan-IIA in facilitating tolerance to hypoxia. A549 cells were pretreated with Tan-IIA and exposed to hypoxia for 6, 12, 24, and 48 h. Biochemical and molecular parameters were assessed in order to trace the signaling pathway. Tan-IIA attenuated hypoxia-induced oxidative stress by modulating the expression of AP-1 subunits (via. MAPK) and Nrf2 transcription factor, which in turn were responsible for maintaining the higher levels of antioxidant enzymes and genes (HO). Tan-IIA increased the cell survival. This could be attributed to an increased NO level via iNOS gene and activated JNK, ERK pathway that induced c-jun/c-fos, c-jun/fosB, junD/c-fos, and junD/fosB heterodimers. This in turn leads to the cell cycle progression by activating cyclins (D and B). This was further confirmed by the lower levels of p53 and their downstream genes (p16, p21, p27). In addition, Tan-IIA decreased pro-inflammatory cytokine levels by inhibiting the formation of junB/fra-1 heterodimer regulated by p38. Tan-IIA increased cell survival to hypoxia by maintaining the higher levels of cellular iNOS, HO-1, jun-D, c-jun, fos B via Nrf2-AP-1.

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Abbreviations

NO:

nitric oxide

iNOS:

inducible nitric oxide synthase

HO-1:

hemeoxygenase-1

ROS:

reactive oxygen species

GSH:

glutathione

SOD-2:

superoxide dismutase-2

ERK:

extracellular signal-regulated kinases

MAPK:

mitogen-activated protein kinase

MT:

metallothionine.

JNK:

c-jun N-terminal kinases

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Acknowledgments

The authors acknowledge Defence Institute of Physiology & Allied Sciences (DIPAS) and Defence Research & Development Organization (DRDO) for providing necessary facilities for the study and Council of Scientific and Industrial Research, India, for providing necessary facilities.

Funding

The Defence Institute of Physiology & Allied Sciences (DIPAS) and Defence Research & Development Organization (DRDO) provided financial support for the study and Council of Scientific and Industrial Research, India, provided funding for this study.

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Authors

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Seema Yadav: performed the experiments and analyzed the results.

Mrinalini Singh: conceived the study and were in charge of overall direction and planning.

Som Nath Singh: supervised the findings of this work.

Bhuvnesh Kumar: supervised the project.

All authors provided critical feedback and helped to shape the research, analysis, and manuscript.

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Correspondence to Mrinalini Singh.

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Yadav, S., Singh, M., Singh, S.N. et al. Tanshinone IIA pretreatment promotes cell survival in human lung epithelial cells under hypoxia via AP-1-Nrf2 transcription factor. Cell Stress and Chaperones 25, 427–440 (2020). https://doi.org/10.1007/s12192-020-01083-3

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  • DOI: https://doi.org/10.1007/s12192-020-01083-3

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