title: The Synthetic Oleanane Triterpenoid HIMOXOL Induces Autophagy in Breast Cancer Cells via ERK1/2 MAPK Pathway and Beclin-1 Up-regulation.
abstract: Autophagy is engaged in tumor growth and progression, but also acts as a cell death and tumor suppression initiator. Naturally-derived compounds and their derivatives constitute a rich source of autophagy modulators. This paper presents the study on the mechanism of action of oleanolic acid derivatives, HIMOXOL and Br-HIMOLID, in MCF7 breast cancer cells. Both compounds reduced MCF7 cell viability more efficiently than the parental compound. It is noteworthy that this effect was specific to MCF7 cancer cells, while in non-cancer MCF-12A cells the cytotoxicity of the studied compounds was significantly lower. Moreover, in contrast to oleanolic acid, the tested compounds were only able to increase autophagy in MCF7 cells. Interestingly, HIMOXOL caused a significantly (p<0.05) higher autophagy rate in MCF7 cells than Br-HIMOLID, as measured by an LC3 immuno-identification study. We also found that HIMOXOL upregulated Beclin-1 expression in MCF7 cells. The observed biological activity of the compound contributed to the modulation of the MAPK ERK1/2 pathway that is engaged in the regulation of autophagy signaling. Importantly, we revealed no proapoptotic activity of the compound in the studied cells. However, autophagy induction in MCF7 cancer cells was reflected in the significantly decreased viability of these cells. Thus, we conclude that HIMOXOL (but not Br-HIMOLID) might reveal a significant potential against breast cancer cells, since it might efficiently induce the main autophagy mediator and prognostic factor, BECN1.
authors.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 49 Przybyszewskiego St, 60-355 Poznan, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lisiak
authors.forename: Ewa
authors.initials: E
authors.lastname: Toton
authors.forename: Blazej
authors.initials: B
authors.lastname: Rubis
authors.forename: Barbara
authors.initials: B
authors.lastname: Majer
authors.forename: Maria
authors.initials: M
authors.lastname: Rybczynska
keywords: Beclin-1; MAPK ERK1/2; Oleanolic acid; autophagy; breast cancer; synthetic triterpenoids