Sinomenine Inhibits the Growth of Ovarian Cancer Cells Through the Suppression of Mitosis by Down-Regulating the Expression and the Activity of CDK1

Abstract

Introduction Ovarian cancer is one of the most common gynecological cancers worldwide. While, therapies against ovarian cancer have not been completely effective, sinomenine has been proved to have anti-tumor activity in various cancer cells. However, study of its anti-ovarian cancer effect is still rare, and the underlying mechanism has not been elucidated. Therefore, we aim to explore the mechanism of sinomenine anti-ovarian cancer. Materials and Methods The effect of anti-ovarian cancer HeyA8 cells was analyzed by CCK8 and colony formation assay. The mechanism of sinomenine anti-ovarian cancer was explored via high throughput RNA-seq, and then the target mRNA and protein expression were verified by real-time PCR and Western blot, respectively. Results We found that the proliferation and clone formation ability of ovarian cancer HeyA8 cells were markedly reduced by 1.56 mM sinomenine. The transcriptome analysis showed that 2679 genes were differentially expressed after sinomenine treatment in HeyA8 cells, including 1323 down-regulated genes and 1356 up-regulated genes. Gene ontology and KEGG pathway enrichment indicated that differential expression genes (DEGs) between the groups of sinomenine and DMSO-treated HeyA8 cells were mainly involved in the process of the cell cycle, such as kinetochore organization, chromosome segregation, and DNA replication. Strikingly, the top 18 ranked degree genes in the protein–protein interaction (PPI) network were mainly involved in the process of mitosis, such as sister chromatid segregation, condensed chromosome, and microtubule cytoskeleton organization. Moreover, real-time PCR results showed consistent expression trends of DEGs with transcriptome analysis. The results of Western blot showed the expression level of CDK1, which was the highest degree gene in PPI and the main regulator controlling the process of mitosis, and the levels of phosphorylated P-CDK (Thr161) and P-Histone H3 (Ser10) were decreased after being treated with sinomenine. Conclusion Our results demonstrated that sinomenine inhibited the proliferation of HeyA8 cells through suppressing mitosis by down-regulating the expression and the activity of CDK1. The study may provide a preliminary research basis for the application of sinomenine in anti-ovarian cancer.

Recent Advances in the Therapeutic Potential of Sinomenine for Cancer Treatment

“…Sinomenine also promotes cell apoptosis through G0/G1 phase arrest [68]. Recent work has shown that sinomenine inhibits HeyA8 cell growth by inhibiting mitosis and modulating its expression and activity [19]. Sinomenine inhibits proliferation and metastasis in ovarian cancer cells in a time-and concentrationdependent manner and may inhibit metastasis while reversing EMT and decreasing β-catenin nuclear accumulation.…”

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review

“…X.Y. Qu and team reported that SIN inhibited the proliferation (IC 50 = 1.56 mM) and colony-formation ability of ovarian cancer HeyA8 cells by downregulating CDK1, reducing p-CDK (Thr161) and p-Histone H3 (Ser10) [ 36 ]. The previous year, F. Gao et al reported the antitumor activity and mechanism of Mufangji decoction (MFJD), of which SIN is a component in preventing lung cancer.…”

“…Another compound 2 (35) (10 mM) displayed neuroprotective effects by inhibiting the oxidative damage induced via β-amyloid 25-35 in PC-12 cells [224]. The authors reported that SIN derivative 3A (36) showed an obvious inhibitory effect on CFLL-2 (IC 50 was 2.3 mM), and the inhibitory rate of NO production on macrophages was 97.1%. It can alleviate hematopoietic cell damage via reducing the activity of stimulated CD8 + T cells, reducing cell surface antigen CD69 expressed via activating T cells, impair aerobic glycolysis, and inhibit the release of IFN-γ and TNF-α in mouse CTL line CFLL-2 [225].…”

Advances in mitophagy and mitochondrial apoptosis pathway-related drugs in glioblastoma treatment

“…SIN has anti-inflammatory effects and has been used to treat rheumatoid diseases in humans (Lin et al, 2022b;Chen et al, 2022). In recent years, SIN and its derivatives have been reported to have strong anti-tumor activity against various tumors, including BC (Xu et al, 2021b), prostate (Xu et al, 2019), papillary thyroid (Zhang et al, 2022b), breast (Li et al, 2022b;Gao et al, 2022), ovarian (Qu et al, 2021), and lung cancers (Bai et al, 2021). SIN can inhibit cell proliferation (Sun et al, 2018a;He et al, 2018), induce apoptosis (Liu et al, 2019) and arrest the cell cycle at the G0/G1 phase in various cancers (Yang et al, 2021a).…”