1.Orlistat induces ferroptosis-like cell death of lung cancer cells.
Wenjing ZHOU ; Jing ZHANG ; Mingkun YAN ; Jin WU ; Shuo LIAN ; Kang SUN ; Baiqing LI ; Jia MA ; Jun XIA ; Chaoqun LIAN
Frontiers of Medicine 2021;15(6):922-932
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.
Animals
;
Cell Death
;
Cell Line, Tumor
;
Ferroptosis
;
Lung Neoplasms/drug therapy*
;
Mice
;
Orlistat