Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma

Abstract

Metformin, an ancient drug commonly used for treating type II diabetes, has been associated to anti-cancer capacity in a variety of developing cancers, though the mechanism remains elusive. Here, we aimed to examine the inhibitory effect of metformin in osteosarcoma. Herein, we demonstrated that metformin treatment blocked proliferation progression by causing accumulation of G2/M phase in U2OS and 143B cells. Furthermore, metformin treatment triggered programmed cell death process in osteosarcoma cell lines. Further research indicated the induction of apoptosis and autophagy triggered by metformin could remarkably attenuate after the treatment of ROS scavenger NAC and JNK inhibitor SP600125. Additionally, our results showed that NAC-suppressed JNK/c-Jun signaling pathway could have been activated through metformin treatment. Lastly, metformin could inhibit osteosarcoma growth under safe dose in vivo. Thus, we propose that metformin could induce cell cycle arrest as well as programmed cell death, including apoptosis and autophagy, through ROS-dependent JNK/c-Jun cascade in human osteosarcoma. This metformin-induced pathway provides further insights into its antitumor potential molecular mechanism and illuminates potential cancer targets for osteosarcoma.

Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells

“…The results of the present study indicated that metformin significantly reduced human cervical cancer cell viability (CaSki, C33A and HeLa) in a dose-dependent manner ( Fig. 1A ), which was consistent with previous studies that demonstrated that metformin significantly reduced the viability of thyroid cancer, osteosarcoma, leukemia and bile duct cancer cells by downregulating the expression of the antiapoptotic protein Bcl-2, and upregulating the expression of the proapoptotic proteins Bak and Bax ( 16 , 48 – 50 ). The present study also indicated that HeLa cells were more sensitive to metformin compared with CaSki and C33A cells, which may be caused by cell-type specificity and mutations in cancer-related genes resulting in resistance to the anti-proliferative effects of metformin.…”

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Apoptosis, also known as type I genetically programmed cell death, is a normal biological process described by stereotypical morphological alterations involving nuclear fragmentation and condensation, membrane blebbing, and apoptotic body formation [ 189 , 190 ]. Two significant apoptosis pathways have been reported: the mitochondria-mediated pathway and death receptor-mediated pathway, which depend on the caspase activation [ 191 ].…”

Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro

“…Briefly, doxorubicin is one of the main drugs used in chemotherapy; it promotes cell death by DNA damage, oxidative stress, and mitochondrial dysfunction [ 36 ]. On the other hand, metformin inhibits complex 1 of the electron transport chain in the mitochondria, activating AMPK and abrogating mTOR phosphorylation, leading to autophagy activation [ 37 ]. Together with this fact, metformin is considered a powerful hypoglycemic that reduces glucose blood levels, promoting a decrease in the metabolic rate [ 38 ].…”