TY - JOUR
T1 - Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer
AU - You, Yanting
AU - He, Qiuxing
AU - Lu, Hanqi
AU - Zhou, Xinghong
AU - Chen, Liqian
AU - Liu, Huaxi
AU - Lu, Zibin
AU - Liu, Dongyi
AU - Liu, Yanyan
AU - Zuo, Daming
AU - FU, Xiuqiong
AU - KWAN, Hiu Yee
AU - Zhao, Xiaoshan
N1 - Funding Information:
This work was supported by the Key Project of National Natural Science Foundation of China (No. 81830117), the National Science Foundation of China (Nos. 81673840 and 81873205), the Natural Science Foundation of Guangdong Province, China (Nos. 2017A030313791 and 2017A030313750), and the Science & Technical Plan of Guangzhou, Guangdong, China (No. 201804010118).
PY - 2020/3/12
Y1 - 2020/3/12
N2 - 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.
AB - 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.
KW - cervical cancer
KW - dynamin-related protein 1
KW - G2/M cell cycle arrest
KW - mitochondria fission
KW - silibinin
UR - http://www.scopus.com/inward/record.url?scp=85082725357&partnerID=8YFLogxK
U2 - 10.3389/fphar.2020.00271
DO - 10.3389/fphar.2020.00271
M3 - Article
AN - SCOPUS:85082725357
VL - 11
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - 271
ER -