Matrine is a natural alkaloid isolated from the root and stem of the legume plant Sophora. Its anti-proliferative and pro-apoptotic effects on several types of cancer have been well-documented. However, the role of matrine in regulating mitochondrial homeostasis, particularly mitophagy in liver cancer apoptosis, remains uncertain. The aim of our study was to explore whether matrine promotes liver cancer cell apoptosis by modifying mitophagy. HepG2 cells were used in the study and treated with different doses of matrine. Cell viability and apoptosis were determined by MTT assay, TUNEL staining, western blotting, and LDH release assay. Mitophagy was monitored by immunofluorescence assay and western blotting. Mitochondrial function was assessed by immunofluorescence assay, ELISA, and western blotting. The results of our study indicated that matrine treatment dose-dependently reduced cell viability and increased the apoptotic rate of HepG2 cells. Functional studies demonstrated that matrine treatment induced mitochondrial dysfunction and activated mitochondrial apoptosis by inhibiting protective mitophagy. Re-activation of mitophagy abolished the pro-apoptotic effects of matrine on HepG2 cells. Molecular investigations further confirmed that matrine regulated mitophagy via the PINK1/Parkin pathways. Matrine blocked the PINK1/Parkin pathways and repressed mitophagy, whereas activation of the PINK1/Parkin pathways increased mitophagy activity and promoted HepG2 cell survival in the presence of matrine. Together, our data indicated that matrine promoted HepG2 cell apoptosis through a novel mechanism that acted via inhibiting mitophagy and the PINK1/Parkin pathways. This finding provides new insight into the molecular mechanism of matrine for treating liver cancer and offers a potential target to repress liver cancer progression by modulating mitophagy and the PINK1/Parkin pathways.
Mitochondrial homeostasis is closely associated with liver cancer progression via multiple mechanisms and is also a potential tumour-suppressive target in clinical practice. However, the role of mitochondrial fission in liver cancer cell viability has not been adequately investigated. Matrine, a type of alkaloid isolated from Sophora flavescens, has been widely used to treat various types of cancer. However, the molecular effect of matrine on mitochondrial homeostasis is unclear. Therefore, the aim of the current study was to determine the role of mitochondrial fission in cell apoptosis, viability, migration and proliferation of HepG2 cells in vitro. The effect of matrine on mitochondrial fission and its mechanism were also explored. The results of our study showed that HepG2 cells treated with matrine had reduced viability, an increased apoptotic rate, a blunted migratory response, and impaired proliferation capacity. At the molecular level, matrine treatment activated mitochondrial fission, which promoted mitochondrial dysfunction, caused cellular oxidative stress, disrupted cellular energy metabolism and initiated cell apoptotic pathways. However, blockade of mitochondrial fission abolished the deleterious effects of matrine on HepG2 cells. Further, we demonstrated that the Mst1-JNK signalling axis was required for matrine-modulated mitochondrial fission. Matrine-mediated mitochondrial dysfunction was reversed by inhibiting Mst1-JNK pathways. Together, our results demonstrated that mitochondrial fission could be a potential upstream tumour-suppressive signal for liver cancer by modifying mitochondrial function and cell death. By contrast, matrine exerted an anticancer function in liver cancer by activating mitochondrial fission mediated by Mst1-JNK pathways.
The Editor-in-Chief has retracted this article (Wei et al. 2018) because of significant concerns regarding a number of Figures presented in this work, that question the integrity of the data. After publication, overlap was detected with figures in articles submitted and published within a close time frame. Specifically, elements of Fig. 2 appear to be identical to Fig. 2 in an article published by the same authors (Cao et al. 2019).Figure 1 and 2 appear similar to Figs. 1 and 2 respectively in an article by different authors (Jieensinue et al. 2018). Furthermore, it appears one image from Fig. 2a (Matrine 1 nM) has been flipped and re-used in Fig. 6 J as Tan IIA 5uM in Jieensinue et al. (2018). The same image appears to have been also used in Fig. 6A in Cao et al. (2019).
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