TY - JOUR
T1 - Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy
AU - Tang, Yancheng
AU - Wang, Liming
AU - Yi, Tao
AU - Xu, Jun
AU - Wang, Jigang
AU - Qin, Jiang Jiang
AU - Chen, Qilei
AU - Yip, Ka Man
AU - Pan, Yihang
AU - Hong, Peng
AU - Lu, Yingying
AU - Shen, Han Ming
AU - Chen, Hu Biao
N1 - Funding Information:
This work was supported by research grants from Innovation and Technology Fund ( PRP/036/20FX , China) and Health and Medical Research Fund ( MHRF-16170251 , China) of Hong Kong to Hu-Biao Chen, Singapore Ministry of Education (MOE) Tier 2 ( MOE2018-T2-1-060 , Singapore) to Han-Ming Shen, National Natural Science Foundation of China ( 82074123 to Hu-Biao Chen; 31501116 to Yingying Lu; 82071441 to Liming Wang). We thank members of Chen's laboratory and Shen's laboratory for valuable discussion. We gratefully thank the support from Dr. Richard Youle for providing the YFP-Parkin-HeLa cells; Dr. Noboru Mizushima for providing the GFP-LC3B-HeLa cells. We thank Dr. Martha Dahlen for polishing this manuscript.
Publisher Copyright:
© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
PY - 2021/12
Y1 - 2021/12
N2 - Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.
AB - Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.
KW - Apoptosis
KW - Combination therapy
KW - Magnolol
KW - PINK1‒Parkin-mediated mitophagy
KW - Tumor suppression
UR - http://www.scopus.com/inward/record.url?scp=85114639104&partnerID=8YFLogxK
U2 - 10.1016/j.apsb.2021.06.007
DO - 10.1016/j.apsb.2021.06.007
M3 - Journal article
AN - SCOPUS:85114639104
SN - 2211-3835
VL - 11
SP - 3966
EP - 3982
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 12
ER -