Apatinib induced ferroptosis by lipid peroxidation in gastric cancer

Abstract

Background

Apatinib, a competitive inhibitor of VEGFR2, has anti-angiogenesis and anticancer activities through different mechanisms, but it still cannot fully explain the drug efficacy of apatinib. Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in cancer biology, however, the exact role of ferroptosis in apatinib-mediating anticancer treatment are still not clear.

Methods

The effects of (1S, 3R)-RSL3 and apatinib were evaluated in different GC cell lines and in normal human gastric epithelial cells. Further, the effects of apatinib and inhibition of antioxidant defense enzyme glutathione peroxidase (GPX4) on cell viability, cell death, glutathione (GSH) levels, lipid ROS production, cellular malondialdehyde (MDA) levels and protein expression were evaluated in vitro as well as in a mouse tumor xenograft model. The expression level of GPX4 in GC tissues and paracancerous tissues was measured by immunohistochemistry.

Results

(1S, 3R)-RSL3 selectively killed GC cells, but not normal cells. Apatinib induced ferroptosis in GC cells by decreasing cellular GSH levels and increasing lipid peroxidation levels. This effect was blocked by co-incubation with ferrostatin-1, liproxstatin-1, GSH, or vitamin E. Further investigation revealed that apatinib down-regulated GPX4 expression via inhibition of the transcription factors Sterol regulatory element-binding protein-1a (SREBP-1a). Besides, we found that multi-drug resistant GC cells were vulnerable to apatinib-induced GPX4 inhibition.

Conclusions

In summary, we show that apatinib could induce the lipid peroxidation through GPX4 mediated by SREBP-1a, then negatively regulate the GC cell, even the multi-drug-resistant GC cell, ferroptosis.

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Availability of data and materials

All data and details can be obtained by contacting the corresponding author.

Abbreviations

GC:

Gastric cancer

GPX4:

Glutathione peroxidase 4

GSH:

Glutathione

GSSG:

Glutathione disulfide

ROS:

Reactive oxygen species

RSL3:

RAS-selective lethal3

MDA:

Malondialdehyde

Fer-1:

Ferrostatin-1

DFO:

Deferoxamine

Lip-1:

Liproxstatin-1

siRNA:

Short interfering RNA

PBS:

Phosphate-buffered saline

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Funding

This work was supported by the National Natural Science Foundation of China (81772133 to QM and 81902444 to LYZ); the Guangdong Natural Science Fund (2020A1515010269 to LYZ and 2020A1515011367 to QM); the Guangzhou Citizen Health Science and Technology Research Project (201803010034 to QM and 201903010072 to LYZ).

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Authors

Contributions

QM, GXL, and LYZ conceived of and designed the experiments. LYZ, YMP, SXH, RL, ZQW, JHH, and XTL performed the experiments. LYZ, YMP and SXH analyzed the data. QM contributed reagents/materials/analysis tools. LYZ and YMP wrote the draft, and made all revisions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Guoxin Li.

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All procedures involving animals and their care in this study were undertaken in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the Southern Medical University Institutional Animal Care and Use Committee.

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Cite this article

Zhao, L., Peng, Y., He, S. et al. Apatinib induced ferroptosis by lipid peroxidation in gastric cancer. Gastric Cancer (2021). https://doi.org/10.1007/s10120-021-01159-8

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Keywords

  • Gastric cancer
  • Apatinib
  • Ferroptosis
  • GPX4
  • Lipid peroxidation