Matrine has pro-apoptotic effects on liver cancer by triggering mitochondrial fission and activating Mst1-JNK signalling pathways

Abstract

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.

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“…In lung cancer, overexpression of Mst1 affects the feedback loop of p53 and JNK and ultimately exacerbates cancer cell death (Landry et al 2017). Moreover, Mst1 is a downstream effector of several anti-cancer drugs such as matrine (Cao et al 2018) and taurine. Recently, careful studies from several laboratories have further demonstrated that Mst1 regulates cell viability by targeting mitochondria (Zhou et al 2018c).…”

The Ethanol Supernatant Extracts of Liushenwan Could Alleviate Nanodiethylnitrosamine-Induced Liver Cancer in Mice

“…These data underscored the urgent need to develop more effective therapies against liver cancer. Recently, many potential new compounds have been demonstrated to possess anticancer cell abilities, including ailanthone [ 33 ], botulin [ 34 ], and matrine [ 35 ]. However, in vivo experiments were still needed for better illustration of their efficacies.…”

Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

“…However, limited attempts have been reported so far in clinical studies, implying a potential high risk and uncertainty of this anti-cancer strategy. Curiously, it has been recently reported that an excess of fission promotes mitochondrial dysfunction, which may play an unfavorable role in cancer cell growth 18 . Therefore, pharmacological induction of mitochondrial fission could provide novel insight into anti-cancer therapy, but this concept has not yet been adequately validated.…”