Orlistat induces ferroptosis-like cell death of lung cancer cells  

作　　者：Wenjing Zhou Jing Zhang Mingkun Yan Jin Wu Shuo Lian Kang Sun Baiqing Li Jia Ma Jun Xia Chaoqun Lian 

机构地区：[1]Research Center of Clinical Laboratory Science,Bengbu Medical College,Bengbu,233030,China [2]Department of Biochemistry and Molecular Biology,School of Laboratory Medicine,Bengbu Medical College,Bengbu,233030,China [3]Department of Genetics,School of Life Sciences,Bengbu Medical College,Bengbu,233000,China [4]Department of Clinical Medicine,Bengbu Medical College,Bengbu,233000,China [5]Anhui Key Laboratory of Infection and Immunity,Bengbu Medical College,Bengbu,233030,China

出　　处：《Frontiers of Medicine》2021年第6期922-932,共11页医学前沿（英文版）

基　　金：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);National Innovation Program for College Students(Nos.201810367021 and 201710367036).

摘　　要：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.

关 键 词：ORLISTAT ferroptosis FAF2 lung cancer 

分 类 号：R730.5[医药卫生—肿瘤]