Orlistat induces ferroptosis-like cell death of lung cancer cells

Abstract

Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P<0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.

Keywords

orlistat / ferroptosis / FAF2 / lung cancer

References

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81672314), the Key Natural Science Project of Anhui Provincial Education Department (No. KJ2020A1244, KJ2020A0578, and KJ2018A0221), and National Innovation Program for College Students (Nos. 201810367021 and 201710367036).

Compliance with ethics guidelines

Wenjing Zhou, Jing Zhang, Mingkun Yan, Jin Wu, Shuo Lian, Kang Sun, Baiqing Li, Jia Ma, Jun Xia, and Chaoqun Lian have declared no conflict of interest. The animal studies and procedures were approved by the Institutional Animal Care and Use Committee at Bengbu Medical College.

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