Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation

Lyu，Xin1; Zeng，Lizhong1; Zhang，Hua2; Ke，Yue3; Liu，Xuan1; Zhao，Nannan1; Yuan，Jingyan1; Chen，Guoan4; Yang，Shuanying1

2020-04-01

10.1016/j.lfs.2020.117366

LIFE SCIENCES   影响因子和分区

0024-3205

1879-0631

Background: Hydroxychloroquine exhibits synergistic anticancer properties as an adjuvant. However, the role and molecular mechanisms underlying of HCQ as monotherapy for lung adenocarcinoma (LUAD) have yet to be elucidated. Methods: We assessed the antitumor effects of HCQ in LUAD cells through a series of in vitro and in vivo assays. GEO database and R packages were used to predict molecular mechanisms of HCQ in the treatment of lung adenocarcinoma, followed by verification of gene expression and subcellular localization via immunoblotting, immunofluorescent and immunohistochemistry assays. Results: We showed the phenotypic effects that HCQ inhibited cell growth, induced apoptosis and cell cycle arrest at G1/S transition in A549 and PC-9 cells, which was associated with inhibition of CDK2, CDK4, CyclinD1 and CyclinE, but up-regulation of p21 and p27. Bioinformatic analysis predicted that 63 targets related to HCQ and LUAD were mainly enriched in JAK-STAT and FoxO pathways. Then, we observed that HCQ decreased the phosphorylation of STAT3, but increased the expression of FoxO3a and its accumulation in the nucleus. The specific STAT3 inhibitor cryptotanshinon augmented the HCQ-induced upregulation and nuclear translocation of FoxO3a. In addition, HCQ increased the expression of p27, which was impaired by FoxO3a blockade with siRNA. Finally, ablation of p27 expression abrogated the cytotoxicity of HCQ. More importantly, similar results were further confirmed in vivo. Conclusions: Taken together, this study suggests that STAT3/FoxO3a/p27 signaling pathway is involved in the anticancer effects of HCQ, and provides preliminary evidence for therapeutic prospects of HCQ alone in LUAD.

Bioinformatic analysis FoxO3a Hydroxychloroquine Lung adenocarcinoma p27Kip1 STAT3

SCI

英语

其他

Science and Technology Funds of Shaanxi Province[2017JM8159]

Research & Experimental Medicine ; Pharmacology & Pharmacy

Medicine, Research & Experimental ; Pharmacology & Pharmacy

WOS:000519537200002

PERGAMON-ELSEVIER SCIENCE LTD

BIOLOGY & BIOCHEMISTRY

2-s2.0-85079266239

Scopus

1.Department of Respiratory and Critical Care Medicine,Second Affiliated Hospital,Xi'an Jiaotong University,Xi'an,No. 157, Xiwu Road, Xincheng District,710004,China
2.Department of Obstetrics and Gynecology,Second Affiliated Hospital,Xi'an Jiaotong University,Xi'an,No. 157, Xiwu Road, Xincheng District,710004,China
3.Department of Radiation Oncology,Second Affiliated Hospital,Xi'an Jiaotong University,Xi'an,No. 157, Xiwu Road, Xincheng District,710004,China
4.School of Medicine,Southern University of Science and Technology,Shenzhen,No. 1088, Xueyuan Road, Nanshan District,518055,China

Lyu，Xin,Zeng，Lizhong,Zhang，Hua,et al. Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation[J]. LIFE SCIENCES,2020,246.

Lyu，Xin.,Zeng，Lizhong.,Zhang，Hua.,Ke，Yue.,Liu，Xuan.,...&Yang，Shuanying.(2020).Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation.LIFE SCIENCES,246.

Lyu，Xin,et al."Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation".LIFE SCIENCES 246(2020).