title: The apoptotic effect of simvastatin via the upregulation of BIM in nonsmall cell lung cancer cells.
abstract: OBJECTIVE
  Statins are known to have pleiotropic effects that induce cell death in certain cancer cells. BIM is a member of the bcl-2 gene family, which promotes apoptotic cell death. This study investigated the hypothesis that simvastatin has pro-apoptotic effects in epidermal growth factor receptor (EGFR)-mutated lung cancer cell lines via the upregulation of the expression of the BIM protein.
  
  
  METHODS
  The cytotoxic effects of simvastatin on gefitinib-sensitive (HCC827, E716-A750del) and -resistant (H1975, T790M + L858R) nonsmall cell lung cancer (NSCLC) cells were compared. Cell proliferation and expression of apoptosis-related and EGFR downstream signaling proteins were evaluated. Expression of BIM was compared in H1975 cells after treatment with simvastatin or gefitinib. SiRNA-mediated BIM depletion was performed to confirm whether the cytotoxicity of simvastatin was mediated by the expression of BIM.
  
  
  RESULTS
  H1975 cells showed significantly reduced viability compared with HCC827 cells after treatment with simvastatin (2 μM) for 48 hours. In simvastatin-treated H1975 cells, expression of pro-apoptotic proteins was increased and the phosphorylation of ERK 1/2 (p-ERK 1/2) was reduced. Expression of BIM was suppressed by gefitinib (1 μM) treatment in H1975 cells, but it was significantly increased by treatment with simvastatin. BIM depletion by siRNA transfection enhanced the viability of H1975 cells that received simvastatin treatment and increased their expression of anti-apoptotic proteins.
  
  
  CONCLUSIONS
  Simvastatin restored the expression of BIM to induce apoptotic cell death in NSCLC cells harboring an EGFR-resistant mutation. Our study suggests the potential utility of simvastatin as a BIM-targeted treatment for NSCLC.
authors.affiliation: a Division of Respiratory, Allergy and Critical Care Medicine , Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: a Division of Respiratory, Allergy and Critical Care Medicine , Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Kim
authors.affiliation: b Department of Biochemistry , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Hye In
authors.initials: HI
authors.lastname: Lee
authors.affiliation: c Division of Pulmonary, Critical Care and Sleep Medicine , Department of Internal Medicine, College of Medicine, St. Paul's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Mo
authors.affiliation: d Division of Pulmonary and Critical Care Medicine , Department of Internal Medicine, College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Chang Dong
authors.initials: CD
authors.lastname: Yeo
authors.affiliation: c Division of Pulmonary, Critical Care and Sleep Medicine , Department of Internal Medicine, College of Medicine, St. Paul's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Hyeon Hui
authors.initials: HH
authors.lastname: Kang
authors.affiliation: c Division of Pulmonary, Critical Care and Sleep Medicine , Department of Internal Medicine, College of Medicine, St. Paul's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Hwa Sik
authors.initials: HS
authors.lastname: Moon
authors.affiliation: c Division of Pulmonary, Critical Care and Sleep Medicine , Department of Internal Medicine, College of Medicine, St. Paul's Hospital, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D051017:Apoptosis Regulatory Proteins; D011799:Quinazolines; D019821:Simvastatin; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: BIM: epidermal growth factor receptor; lung cancer; simvastatin