title: Activation of peroxisome proliferator-activated receptor gamma is crucial for antitumoral effects of 6-iodolactone.
abstract: BACKGROUND
  Molecular iodine (I2) exhibits antiproliferative and apoptotic effects on in vivo and in vitro cancer models. These effects are thought to be mediated by an iodinated arachidonic acid derivative, 6-iodolactone (6IL), and one of the proposed mechanisms is that 6IL activates Peroxisome Proliferator-Activated Receptors type gamma (PPARG). These receptors have been implicated in the inhibition of carcinogenic processes, in addition to their classical role in maintaining lipid and glucose homeostasis. The aim of this study was to determine whether PPARG participates in the 6IL antiproliferative and apoptotic effects on the mammary cancer cell line MCF-7.
  
  
  METHODS
  The 6IL/PPARG complex was inhibited by the PPARG antagonist GW9662, in both an endogenous and overexpressed (adenoviral vector infection) context, and stable PPARG-knockdown MCF-7 cells (RNA interference, confirmed with hydrolysis probes and Western blot), were used to corroborate the PPARG participation. 6IL effects on proliferation (measured by Trypan Blue exclusion) and apoptosis (phosphatidylserine identification by flow cytometer) were evaluated in conditions of chemical inhibition (GW9662) and silencing (RNA interference). A wound-healing assay was conducted on wild-type and stable PPARG-knockdown MCF-7 cells to evaluate the antimigrational effect of 6IL. Caspase-8 activity was evaluated to determine if the extrinsic pathway is involved in the effects of 6IL and I2 treatment.
  
  
  RESULTS
  Antiproliferative and pro-apoptotic 6IL effects require the activation of PPARG. In addition, wound-healing assays show that 6IL is able to inhibit MCF-7 cell migration and that PPARG plays a role in this phenomenon. Finally, the data exclude the participation of the extrinsic apoptotic pathway in 6IL- and I2-induced apoptosis.
  
  
  CONCLUSIONS
  These results support the previously proposed mechanism, in which the I2 effects are mediated by 6IL, and they provide further support for the use of I2 as coadjuvant in breast cancer treatment.
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México-Juriquilla, Boulevard Juriquilla 3001, Juriquilla, Querétaro, CP 76230, Mexico. marionava23@unam.mx.
authors.forename: Mario
authors.initials: M
authors.lastname: Nava-Villalba
authors.affiliation: Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico. re.nunez.anita@gmail.com.
authors.forename: Rosa E
authors.initials: RE
authors.lastname: Nuñez-Anita
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México-Juriquilla, Boulevard Juriquilla 3001, Juriquilla, Querétaro, CP 76230, Mexico. bontix77@yahoo.it.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bontempo
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México-Juriquilla, Boulevard Juriquilla 3001, Juriquilla, Querétaro, CP 76230, Mexico. caracev@unam.mx.
authors.forename: Carmen
authors.initials: C
authors.lastname: Aceves
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000008:administration & dosage*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007455:Iodine / Q000008:administration & dosage*; D061986:MCF-7 Cells; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics; D014945:Wound Healing / Q000235:genetics
chemical_list: D047495:PPAR gamma; D016718:Arachidonic Acid; D007455:Iodine