title: Effects of anti-proliferative lichen metabolite, protolichesterinic acid on fatty acid synthase, cell signalling and drug response in breast cancer cells.
abstract: BACKGROUND
  The lichen compound (+)-protolichesterinic acid (+)-PA, isolated from Iceland moss, has anti-proliferative effects on several cancer cell lines. The chemical structure of (+)-PA is similar to a known fatty acid synthase (FASN) inhibitor C75.
  
  
  OBJECTIVE
  To test whether the anti-proliferative activity of (+)-PA is associated with effects on FASN and HER2 (human epidermal growth factor receptor 2) and major signalling pathways. Synergism between (+)-PA and lapatinib, a HER2 active drug, was also evaluated.
  
  
  METHODS
  Pure compound was isolated by preparative high-performance liquid chromatography (HPLC) and purity of (+)-PA analyzed by analytical HPLC. Cell viability was assessed using Crystal violet staining. FASN and HER2 expression was estimated by immunofluorescence. The Meso Scale Discovery (MSD)(®) assay was used to measure activation of ERK1/2 and AKT. Synergism was estimated by the CalcuSyn software.
  
  
  RESULTS
  Treatment with (+)-PA increased FASN expression in SK-BR-3 cells, which overexpress FASN and HER2, implying a compensatory response to inhibition of FASN activity. HER2 expression was decreased suggesting secondary downregulation. ERK1/2 and AKT signalling pathways were inhibited, probably due to reduced levels of HER2. No effects were observed in T-47D cells. Synergism between (+)-PA and lapatinib was observed in the SK-BR-3 cells.
  
  
  CONCLUSIONS
  Results suggest that the primary effect of (+)-PA is inhibition of FASN activity. Synergistic effects with lapatinib were seen only in SK-BR-3 cells, and not T-47D cells, further supporting the notion that (+)-PA acts by inhibiting FASN with secondary effects on HER2 expression and signalling. (+)-PA could therefore be a suitable agent for further testing, alone or in combination treatment against HER2-overexpressing breast cancer.
authors.affiliation: Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Margrét
authors.initials: M
authors.lastname: Bessadóttir
authors.affiliation: Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Edda Á
authors.initials: EÁ
authors.lastname: Skúladóttir
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gowan
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eccles
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Sesselja
authors.initials: S
authors.lastname: Ögmundsdóttir
authors.affiliation: Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. Electronic address: helgaogm@hi.is.
authors.forename: Helga M
authors.initials: HM
authors.lastname: Ogmundsdóttir
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008011:Lichens / Q000737:chemistry*; D015394:Molecular Structure; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015107:4-Butyrolactone; D064429:Fatty Acid Synthases; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C095781:protolichesterinic acid; C508053:ERBB2 protein, human
keywords: Breast cancer; FASN; HER2; Lichen; Protolichesterinic acid