The natural triterpene maslinic acid induces apoptosis in HT29 colon cancer cells by a JNK-p53-dependent mechanism

Abstract

BackgroundMaslinic acid, a pentacyclic triterpene found in the protective wax-like coating of the leaves and fruit of Olea europaea L., is a promising agent for the prevention of colon cancer. We have shown elsewhere that maslinic acid inhibits cell proliferation to a significant extent and activates mitochondrial apoptosis in colon cancer cells. In our latest work we have investigated further this compound's apoptotic molecular mechanism.MethodsWe used HT29 adenocarcinoma cells. Changes genotoxicity were analyzed by single-cell gel electrophoresis (comet assay). The cell cycle was determined by flow cytometry. Finally, changes in protein expression were examined by western blotting. Student's t-test was used for statistical comparison.ResultsHT29 cells treated with maslinic acid showed significant increases in genotoxicity and cell-cycle arrest during the G0/G1 phase after 72 hours' treatment and an apoptotic sub-G0/G1 peak after 96 hours. Nevertheless, the molecular mechanism for this cytotoxic effect of maslinic acid has never been properly explored. We show here that the anti-tumoral activity of maslinic acid might proceed via p53-mediated apoptosis by acting upon the main signaling components that lead to an increase in p53 activity and the induction of the rest of the factors that participate in the apoptotic pathway. We found that in HT29 cells maslinic acid activated the expression of c-Jun NH2-terminal kinase (JNK), thus inducing p53. Treatment of tumor cells with maslinic acid also resulted in an increase in the expression of Bid and Bax, repression of Bcl-2, release of cytochrome-c and an increase in the expression of caspases -9, -3, and -7. Moreover, maslinic acid produced belated caspase-8 activity, thus amplifying the initial mitochondrial apoptotic signaling.ConclusionAll these results suggest that maslinic acid induces apoptosis in human HT29 colon-cancer cells through the JNK-Bid-mediated mitochondrial apoptotic pathway via the activation of p53. Thus we propose a plausible sequential molecular mechanism for the expression of the different proteins responsible for the intrinsic mitochondrial apoptotic pathway. Further studies with other cell lines will be needed to confirm the general nature of these findings.

Amoebicidal Activity of Caffeine and Maslinic Acid by the Induction of Programmed Cell Death in Acanthamoeba

“…However, it is known that caffeine and maslinic acid induce apoptosis in various vertebrate cell types. For example, caffeine induce PCD in neuroblastoma cells and pancreatic and lung adenocarcinomas (27,28,29,30) and maslinic acid induces apoptosis in metastatic cell lines and in colon cancer cells (31,32). We could find no study in which either drug was reported to induce PCD in any protist.…”

Induction of Intrinsic and Extrinsic Apoptosis Pathways in the Human Leukemic MOLT-4 Cell Line by Terpinen-4-ol

“…Truncated-Bid in turn initiates the mitochondrial pathway. Pro-apoptotic Bid targets the mitochondria and regulates other apoptotic-related protein such as Bcl-2, Bcl-xL and Bax (Reyes-Zurita et al, 2011). The intrinsic pathway plays a key role in regulating cell death through mitochondria.…”

Maslinic acid activates mitochondria-dependent apoptotic pathway in cardiac carcinoma

“…Actually, the induction of apoptosis has been documented to be one of the major mechanisms underlying the anti-tumor activity of MA. e apoptotic pathway can be triggered by MA, both in mitochondriadependent and -independent ways [8,11]. e association of p38 MAPK signaling with MA's anti-tumor activity has also been indicated in previous studies.…”