Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers

Haiyang Yu,Yuling Qiu,Chengyun Jin,Xu Pang,Xiumei Gao,Lifeng Han,Tao Wang,Shuangshuang Yin,Shiyue Zhou,Yi Zhang,Jiachen Sun,Yingying Shao

doi:10.1038/s41419-018-0660-4

Abstract

Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.

Highlights

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and leading causes of cancer-related mortality worldwide[1,2]
Molecular validation mechanistically demonstrates that magnolin-induced autophagy and cell cycle arrest in CRC cells is associated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat[3] and represses transcriptional expression of Mcl-1
We have demonstrated that magnolin represses Stat3/Mcl-1 signaling via targeting LIF, and thereby inducing autophagy and cell cycle arrest, leading to the suppression of the growth of CRCs in vitro and in vivo

Summary

Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and leading causes of cancer-related mortality worldwide[1,2]. Despite the benefits of early screening, surgery and other localized therapeutic intervention, the current 5-year survival rate for advanced CRC patients is only 8%3. There is a severe lack of highly reliable strategies for better clinical prevention/therapy. Regorafenib, a novel oral multikinase spectrum inhibitor, has demonstrated effectiveness in patients with chemorefractory metastatic CRC, which progresses though every available standard therapy has been applied[4]. The use of regorafenib is clinically hampered by its modest efficacy in unselected patient populations, serious sideeffects, and high drug costs[4,5]. In order to improve patient outcomes, the development of novel effective and promising strategies for advanced CRC treatment is still urgently needed

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Results

Conclusion