Research Paper Volume 12, Issue 1 pp 138—155

Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer

Man Hu 1, , Zhaomin Yu 1, , Peiyuan Mei 2, , Jinxiao Li 1, , Dan Luo 3, , Haiming Zhang 4, , Minfeng Zhou 5, , Fengxia Liang 5, , Rui Chen 1, ,

  • 1 Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 2 Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 3 Department of Respiratory Medicine, Wuhan First Hospital, Wuhan, China
  • 4 Department of Oncology, Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 5 Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China

received: June 11, 2019 ; accepted: December 5, 2019 ; published: January 3, 2020 ;

https://doi.org/10.18632/aging.102606
How to Cite

Copyright © 2020 Hu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Lycorine is a powerful anti-cancer agent against various cancer cell lines with minor side effects. However, the detailed mechanisms of its effects in colorectal cancer (CRC) remain unclear. In this study, we investigated the function and mechanism of lycorine against CRC both in vitro and in vivo. Molecular docking modeling was used to identify potential inhibitory targets of lycorine in CRC. Cell viability was measured using the Cell Counting Kit-8 assay, and apoptosis was measured using flow cytometry. Autophagosomes were examined using transmission electron microscopy and confocal microscopy. HCT116-derived xenografts were constructed to analyze the effect of lycorine in CRC in vivo. Using the CDOCKER algorithm, we determined that lycorine has four interactions with the conserved domain of mitogen-activated protein kinase kinase 2 (MEK2). This prediction was further confirmed by the degradation of phosphorylated MEK2 and its downstream targets after lycorine treatment, and MEK2 overexpression abolished lycorine-induced autophagy-associated apoptosis. Additionally, we revealed that the combination of vemurafenib and lycorine had better effects in CRC models in vitro and in vivo than monotherapy. Our findings identified lycorine as an effective MEK2 inhibitor and suggested that the combination of lycorine and vemurafenib could be used to treat CRC.

Abbreviations

CRC: colorectal cancer; MEK2: mitogen-activated protein kinase kinase 2; MAPK: mitogen-activated protein kinase; Bax: Bcl-2-associated X protein; TEM: transmission electron microscopy.