Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

Abstract

Cervical cancer is the fourth leading cancer type and the second most common gynecological malignancy among women worldwide. Silibinin (SB), a chief bioactive natural polyphenolic flavonoid of Silybum marianum L., has been used clinically for its hepatocyte protective effects. It also has anticancer effects via the induction of apoptosis and cell cycle arrest. However, the effects of SB on cervical cancer cells through mitochondrial fission have not been studied. Here, we showed that SB markedly suppressed cervical cell proliferation by inducing G2/M cell cycle arrest via the activation of dynamin-related protein 1 (Drp1), which in turn mediated the mitochondrial fission dysfunction both in vitro and in vivo. SB decreased the ATP content, mitochondrial membrane potential, and mtDNA copy number, as well as reduced the reactive oxygen species levels in cervical cells. Furthermore, SB induced excessive mitochondrial fragmentation and reduced tubule formation. Further study showed that knockdown of Drp1 abolished the SB-induced G2/M cell cycle arrest in cervical cancer cells by inhibiting the mitochondrial fission pathway. More importantly, SB inhibited Hela cell growth in vivo model. In conclusion, we are the first to demonstrate that SB induces cervical cancer cell G2/M cell cycle arrest by activating Drp1-dependent mitochondrial fission dysfunction. This study suggests the strategy of inducing Drp1-dependent mitochondrial fission for cervical cancer prevention and treatment.

The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis

“…Previous reports showed that the activity of Drp1 is modulated by G2/M cell cycle arrest [ 35 , 36 ]. The effects of ROT on mitochondrial dysfunction in cancer have been reported [ 17 ].…”

“…Since decreased membrane potential, reduced ATP production, and increased ROS are the three common hallmarks triggering apoptosis, ongoing mitophagy during mitotic arrest (by mito-Drp1-Ser637) may simply represent leaky degradation from incompletely blocked autophagy, which is functionally relevant during prolonged mitotic arrest but likely negligible during normal mitotic progression (Drp1-Ser616). Eventually, this mechanism may also participate in pushing cells with mitotic abnormalities toward cell aneuploidy or cell death ( Figure 8 and right side in Supplementary Figure S8 ) [ 11 , 35 , 51 , 52 , 53 , 54 ]. We showed that ETC and Drp1 inhibitors affect the dynamic interplay between mito-Drp1-Ser637 and mito-Drp1-Ser616 (Ser637/Ser616 ratio) via the PINK1/Parkin pathway to drive mitophagy.…”

Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells

“…The major cyclins have functionally or molecularly links with Drp1 activity 33 . In the previous study, we found that SB inhibited cervical cancer cell proliferation through inducing G2/M cell cycle arrest via activation of the Drp1 34 . In this study, SB promoted normal cell proliferation through facilitating G1/S transition.…”

Optimization of PhysicoChemical Parameters for Production of Cytotoxic Secondary Metabolites and Apoptosis Induction Activities in the Culture Extract of a Marine Algal–Derived Endophytic Fungus Aspergillus sp.

“…The connection with the apoptosis and cell cycle arises from the multiple indications that cell cycle progression alteration may either block or trigger apoptosis ( Pucci et al, 2000 ). Natural products are known to induce G2/M phase arrest, thereby inducing apoptosis ( Hnit et al, 2020 ; You et al, 2020 ). Astuti et al, (2016) observed apoptosis-mediated cell death by endophytic Aspergillus sp,, isolated from Piper crocatum after inducing S phase cell cycle arrest.…”