title: Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer.
abstract: OBJECTIVE
  Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically.
  
  
  METHODS
  We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and β) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL).
  
  
  RESULTS
  Levels of pSTAT3, STAT3α, and STATβ were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3β, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47-78% reduction in anchorage-dependent and anchorage-independent growth and a 28-45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30 μM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25-60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06 to 52.44 μM and 0.86 to 11.66 μM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins.
  
  
  CONCLUSIONS
  STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment.
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Lewis
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Uddalak
authors.initials: U
authors.lastname: Bharadwaj
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: T Kris
authors.initials: TK
authors.lastname: Eckols
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kolosov
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Moses M
authors.initials: MM
authors.lastname: Kasembeli
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Fridley
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Siller
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: DJTweardy@mdanderson.org.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor
keywords: NSCLC; STAT3; Small molecule inhibitors