The Aryl Hydrocarbon Receptor Ligand 6-Formylindolo(3,2-b)carbazole Promotes Estrogen Receptor Alpha and c-Fos Protein Degradation and Inhibits MCF-7 Cell Proliferation and Migration.

INTRODUCTION: Worldwide, breast cancer is the most common cancer in women and is the main cause of death among all neoplasia in this group. Luminal A breast cancer represents approximately 70% of all breast cancers and is treated with hormone therapies targeting estrogen receptor alpha (ERα). Unfortunately, patients develop drug resistance leading to recurrence of neoplasia due to estrogen-independent ERα reactivation. Therefore, it is crucial to identify new molecular targets downstream ERα signaling pathway that allows the implementation of better treatments to improve the outcome of breast cancer patients. Overexpression of c-Fos, an ERα gene target, has been associated with increased cell motility, malignancy, metastasis, and invasion while its neutralization results in decreased breast cancer tumorigenesis. The aryl hydrocarbon receptor (AHR) ligands halogenated and polycyclic aromatic hydrocarbons, highly toxic compounds, down regulate c-Fos and ERα levels. The present study aimed to evaluate whether 6-formylindolo(3,2-b)carbazole (FICZ), a no toxic AHR agonist, modifies c-Fos levels in MCF-7 mammary carcinoma cells as well as to determine its effects on cell proliferation and migration. In addition, the possible mechanism through which FICZ mediates c-Fos levels in MCF-7 cells was investigated. METHODS: Initially, the effect of FICZ on c-Fos mRNA and protein levels in MCF-7 cells, untreated or treated with estradiol, was evaluated by qPCR and Western blot. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin, an AHR prototype agonist, was used as a positive control. Next, we examined the effect of FICZ on MCF-7 cell proliferation and migration by cell counting, MTT, 3H-thymidine incorporation, and scratch-wound assays. Finally, the involvement of proteasome 26S on ERα and c-Fos protein degradation was investigated by the use of MG132 and Western blot. RESULTS: The data show that FICZ treatment downregulates c-Fos mRNA and protein levels, most likely by promoting ERα proteasome degradation, blocking MCF-7 cell proliferation and migration. The results also demonstrate that liganded ERα was required for FICZ-mediated ERα degradation. CONCLUSIONS: Activation of AHR results in a decreased MCF-7 cell proliferation and migration by ERα and c-Fos down regulation. Targeting AHR might be a promising therapy for breast cancer treatment, particularly when estrogen-independent ERα reactivation presents.

Proteomic analysis of Plasmodium berghei in the ring phase during in vivo antiparasitic treatment with kramecyne.

Malaria is a parasitic disease of global importance due to its high annual death toll. The treatment for this infection is difficult for the increase in the populations of parasites resistant to the existing medicines, the development of new antimalarials is urgent needed. Several products developed for the control of malaria from herbalist have had a profound impact, for example, quinine obtained from the bark of the cinchona tree and recently those derived from artemisinin, whose discovery was the reason for the awarding of the 2015 Nobel Prize. The aim of the present study was to evaluate a compound named kramecyne extracted of "chayotillo" (Krameria cystisoides) plant used by the antiparasitic effect against some blood and intestinal protozoa (Giardia duodenalis y Trypanosoma cruzi). In addition is using for the treatment of inflammatory diseases. Measuring parasitaemia at different times, it was observed that in mice treated with kramecyne, it reached only 14% of parasitaemia at 7 days with a dose of 15 mg/kg, using chloroquine as a control drug, because it has not been demonstrated that parasites that infect rodents have developed resistance against this drug. Our results showed that kramecyne decreases the expression of parasite proteins that participate in biological processes, such as invasion, cytoadherence, pathogenicity and energy metabolism. With these results, it is proposed that this compound has repercussions on the metabolism of the parasite and could be useful for use as an antimalarial.