Silibinin triggers apoptotic signaling pathways and autophagic survival response in human colon adenocarcinoma cells and their derived metastatic cells |
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Authors: | Henriette Kauntz Souad Bousserouel Francine Gossé Francis Raul |
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Institution: | 1.Laboratory of Nutritional Cancer Prevention,University of Strasbourg,Strasbourg-Cedex,France |
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Abstract: | Silibinin, a flavonolignan isolated from the milk thistle plant (Silybum marianum), possesses anti-neoplastic properties. In vitro and in vivo studies have recently shown that silibinin inhibits the growth
of colorectal cancer (CRC). The present study investigates the mechanisms of silibinin-induced cell death using an in vitro
model of human colon cancer progression, consisting of primary tumor cells (SW480) and their derived metastatic cells (SW620)
isolated from a metastasis of the same patient. Silibinin induced apoptotic cell death evidenced by DNA fragmentation and
activation of caspase-3 in both cell lines. Silibinin enhanced the expression (protein and mRNA) of TNF-related apoptosis-inducing
ligand (TRAIL) death receptors (DR4/DR5) at the cell surface in SW480 cells, and induced their expression in TRAIL-resistant
SW620 cells normally not expressing DR4/DR5. Caspase-8 and -10 were activated demonstrating the involvement of the extrinsic
apoptotic pathway in silibinin-treated SW480 and SW620 cells. The protein Bid was cleaved in SW480 cells indicating a cross-talk
between extrinsic and intrinsic apoptotic pathway. We demonstrated that silibinin activated also the intrinsic apoptotic pathway
in both cell lines, including the perturbation of the mitochondrial membrane potential, the release of cytochrome c into the
cytosol and the activation of caspase-9. Simultaneously to apoptosis, silibinin triggered an autophagic response. The inhibition
of autophagy with a specific inhibitor enhanced cell death, suggesting a cytoprotective function for autophagy in silibinin-treated
cells. Taken together, our data show that silibinin initiated in SW480 and SW620 cells an autophagic-mediated survival response
overwhelmed by the activation of both the extrinsic and intrinsic apoptotic pathways. |
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