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Tumor Biology

, Volume 37, Issue 8, pp 10403–10413 | Cite as

A novel derivative of tetrandrine (H1) induces endoplasmic reticulum stress-mediated apoptosis and prosurvival autophagy in human non-small cell lung cancer cells

  • Yidan Lin
  • Yu Wang
  • Xianfang Liu
  • Jiamei Yan
  • Ling Su
  • Xiangguo Liu
Original Article

Abstract

H1, a bromized derivative of tetrandrine, has been reported to induce apoptosis in human cancer cells. But, the underlying mechanism of apoptosis triggered by H1 is unclear. In the present study, we found that H1 triggered death receptor 5 (DR5)-dependent apoptosis in non-small cell lung cancer (NSCLC) cells. Further study showed that H1 activated ER stress through enforcing the expression of Bip/GRP78, IRE1α, p-eIF2α, and CHOP. Moreover, abrogating CHOP expression blocked DR5 upregulation and subsequent apoptosis, indicating that CHOP was essential for DR5-dependent apoptosis induced by H1. In addition, H1 greatly downregulated cellular FLICE-inhibitory protein (c-FLIP), and enhanced expression of c-FLIP protected cancer cells from apoptosis in spite of H1 therapy. Furthermore, we discovered that H1 induced autophagy in human NSCLC cells. Interestingly, the autophagy induced by H1 played a protective function in NSCLC cells and effectively weakened caspase-mediated apoptosis. In summary, these findings suggest that H1 induces DR5-dependent apoptosis in human NSCLC cells via stimulating ER stress signaling pathway, and pharmacologically inhibiting autophagy will be an efficient approach to synergize H1-caused apoptosis in lung cancer cells.

Keywords

Tetrandrine Apoptosis Autophagy DR5 CHOP c-FLIP ER stress 

Abbreviations

CHOP

C/EBP homologous protein

NSCLC

Non-small cell lung cancer

DR5

Death receptor 5

TRAIL

TNF-related apoptosis-inducing ligand

c-FLIP

Cellular FLICE-inhibitory protein

caspase-8

Apoptosis-related cysteine peptidase

caspase-3

Apoptosis-related cysteine peptidase

PARP

Poly (ADP-ribose) polymerase

MDR

Multidrug resistance

tBid

The truncated form of Bid

DISC

Death-inducing signal complex

SRB

Sulforhodamine B

PE

Phosphatidylethanolamine

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31371402, 31071210, 31171332, 81472686). We thank Prof. Fengpeng Wang, West China College of Pharmacy, Sichuan University, China. He kindly provided the synthesized H1 to us for this study.

Compliance with ethical standards

Conflict of interest

None.

Supplementary material

13277_2016_4950_MOESM1_ESM.docx (14 kb)
ESM 1 Figure S1. H1 induces apoptosis in human NSCLC cells by flow cytometry analysis. H1792, A549 and Calu-1 cells were treated with H1 at various concentrations (0, 5, 10 and 20 μM) for 24h. The flow cytometry analysis was performed to detect the apoptosis after staining with Annexin-V-FITC and PI. Representative plots are shown. Columns: mean of triplicate treatments; bars: ± SD. (DOCX 13 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Yidan Lin
    • 1
  • Yu Wang
    • 2
  • Xianfang Liu
    • 3
  • Jiamei Yan
    • 2
  • Ling Su
    • 2
  • Xiangguo Liu
    • 2
  1. 1.The Thoracic Surgery Department of West China HospitalWest China Medical School of Sichuan UniversityChengduChina
  2. 2.The Provincial Key Laboratory of Animal Cells and Developmental BiologySchool of Life Sciences, Shandong UniversityJinanChina
  3. 3.The Department of Otolaryngology Head and Neck SurgeryProvincial Hospital Affiliated to Shandong UniversityJinanChina

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