Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress.
Breast cancer is the leading cause of cancer death among females, and novel chemotherapeutic drugs for treating breast cancer are needed urgently. Saxifragifolin D (SD) was isolated by our group from Androsace umbellata which is commonly used to treat solid tumor. In this study, we evaluated its growth inhibitory effect on breast cancer cells and explored the underlying molecular mechanisms. Our results showed that SD inhibited the growth of both MCF-7 and MDA-MB-231 cells significantly. Mechanistic studies demonstrated that SD induced apoptosis through mitochondrial apoptotic pathway. Evidence of SD-induced autophagy included the occurrence of autophagic vacuoles, up-regulation of LC3-II, Beclin1 and Vps34. Inhibition of autophagy by bafilomycin A1 or Beclin1 siRNA pretreatment decreased the ratio of apoptosis, indicating that autophagy induction contributes to apoptosis and is required for the latter. SD was also found to induce endoplasmic reticulum stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of Bip, IRE1α and XBP-1s. Inhibition of endoplasmic reticulum stress by N-acetyl-l-cysteine, tauroursodeoxycholic acid or IRE1α siRNA pretreatment could suppress both apoptosis and autophagy. Besides, increases in CHOP, calnexin, calpain, p-JNK and p-Bcl-2 were followed by subsequent dissociation of Beclin1 from Bcl-2, further suggesting endoplasmic reticulum stress to be the common signaling pathway shared by SD-induced apoptosis and autophagy. In conclusion, SD inhibits breast cancer cell growth and induces interplay between apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress. It will provide molecular bases for developing SD into a drug candidate for the treatment of breast cancer.
College of Pharmacy, Jinan University, Guangzhou 510632, China.
Jun-Min
JM
Shi
Liang-Liang
LL
Bai
Dong-Mei
DM
Zhang
Anita
A
Yiu
Zhi-Qi
ZQ
Yin
Wei-Li
WL
Han
Jun-Shan
JS
Liu
Yong
Y
Li
Deng-Yue
DY
Fu
Wen-Cai
WC
Ye
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D012503:Saponins; C580883:saxifragifolin D; D002118:Calcium