Abstract
The development of acquired resistance to pro-apoptotic antitumor agents is a major impediment to the cure of cholangiocarcinoma (CCA). Antitumor drugs inducing non-apoptotic cell death are considered as a new approach to overcome such drug resistance. Here, we reported for the first time that matrine-induced necroptosis in CCA cell lines, differing from its classical role to induce apoptosis in many other kinds of cancer cells. CCA cells under matrine treatment exhibited typical necrosis-like but not apoptotic morphologic change. These matrine-induced morphologic change and cell death in CCA cells were greatly attenuated by necroptosis inhibitor necrostatin-1, but not apoptosis inhibitor z-VAD-fmk. Unlike many cancer cells with negative receptor-interacting protein 3 (RIP3) expression, moderate expression of RIP3 in CCA cells was observed and was required for matrine to induce necroptosis, which was switched to apoptosis after knocking down endogenous RIP3. Moreover, matrine could increase RIP3 expression level, which may facilitate the necroptosis process. Translocation of mixed lineage kinase-domain like (MLKL) from cytoplasm to plasma membrane as a downstream event of RIP3, as well as the increased production of reactive oxygen species (ROS) by RIP3/MLKL, was critical for matrine to induce necroptosis. In clinical study, we found RIP3 was lower but still moderately expressed in most CCA tissue samples compared with adjacent normal tissues. Taken together, we identified matrine as a necroptosis inducer in CCA by enhancing RIP3 expression and the following RIP3/MLKL/ROS signaling pathway, which provided new individualized strategies based on RIP3 expression to overcome chemoresistance in CCA therapy.
Highlights
Cholangiocarcinoma (CCA) is one of the most common malignant tumors
Matrine-induced necroptosis but not apoptosis in CCA cells electron microscope was performed to determine which kind of cell death was induced by matrine in CCA cells
Flow cytometry analysis indicated that matrine-induced necroptosis but not apoptosis in QBC939, Mz-ChA-1 and HT-29 cell lines with positive receptor-interacting protein 3 (RIP3) expression (Figures 2a and b and Supplementary Figure S1a); in contrast, apoptosis but not necroptosis was induced by matrine in HeLa and MCF-7 cell lines with silenced RIP3 expression (Supplementary Figures S1b and c). These results suggested that the presence of RIP3 protein might switch the cell death from apoptosis to necroptosis when cancer cells were treated with matrine
Summary
Cholangiocarcinoma (CCA) is one of the most common malignant tumors. Epidemiological data revealed that the incidence and mortality of CCA were increasing gradually during last three decades.[1]. The nuclei of HeLa cells present study, a novel role of matrine, to induce necroptosis, was displayed such typical apoptotic features in both the uncovered in CCA QBC939 and Mz-ChA-1 cell lines. The above data indicated that matrine-induced necroptosis but not apoptosis in CCA cell lines.
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