Activation of peroxisome proliferator-activated receptor gamma is crucial for antitumoral effects of 6-iodolactone

Abstract

BackgroundMolecular 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.MethodsThe 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.ResultsAntiproliferative 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.ConclusionsThese 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.

Antiproliferative/cytotoxic effects of molecular iodine, povidone-iodine and Lugol's solution in different human carcinoma cell lines

“…KJ was found to have no effect, but at high concentrations enhances the antiproliferative/cytotoxic effect of molecular iodine. Although the mechanisms of action were not analysed here, it is most likely that mitochondrial-mediated apoptosis pathways are involved as previously described for I 2 and iodolactones (6,(9)(10)(11)(12)(13).…”

24-Methylenecycloartanyl Ferulate Induces PPAR-γ2 Mediated Regulation of Angiogenesis-Related Genes and Inhibits Akt/mTOR Signaling

“…Our previous results show that 24-MCF-induced PPAR-γ2 increases parvin-β expression, which inhibits oncogenic ILK signaling, anchorage-independent growth, and cell migration [4]. A recent study established PPARs as a group of ligand-activated transcriptional regulators that sit at the intersection of genes and the dietary environment [27]. Thus, PPARγ has shown predominately anti-angiogenic properties in vitro and in animal models [27].…”

“…A recent study established PPARs as a group of ligand-activated transcriptional regulators that sit at the intersection of genes and the dietary environment [27]. Thus, PPARγ has shown predominately anti-angiogenic properties in vitro and in animal models [27]. Therefore, some research has examined the PPARγ activating potential of a wide range of natural products originating from traditionally used medicinal plants and dietary sources [17].…”

Adjuvant Effect of Molecular Iodine in Conventional Chemotherapy for Breast Cancer. Randomized Pilot Study

“…The expression of CDKN1A (P21), BAX, BCL2, BIRC5 (Survivin), and HIF1A was analyzed by quantitative real-time PCR (RT-qPCR) as described previously [16]. Total RNA was obtained using TRIZOL reagent (Life Technologies, Inc., Carlsbad, CA), and the extracted RNA (2 μg) was reverse transcribed using oligo-deoxythymidine primers (RT).…”

“…VEGF, PPARG, and actin protein expression levels were analyzed using a commercial kit (Roche Diagnostics GmbH, Mannheim, Germany) as described previously (16). The membranes were treated with a polyclonal anti-VEGF antibody (SC-7269, diluted 1:1000; secondary antibody -SC-2060; diluted 1:500), a polyclonal anti-PPARG (SC7196, diluted 1:1000; secondary antibody SC-2004, diluted 1:500) and a polyclonal anti-actin antibody (SC-1616, diluted 1:10,000; secondary antibody SC-2020, diluted 1:1000) (all antibodies were from Santa Cruz Biotechnology Inc, Texas, USA.).…”