Oncotarget

Research Papers:

Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death

Betty Yuen Kwan Law, Flora Gordillo-Martnez, Yuan Qing Qu, Ni Zhang, Su Wei Xu, Paolo Saul Coghi, Simon Wing Fai Mok, Jianru Guo, Wei Zhang, Elaine Lai Han Leung, Xing Xing Fan, An Guo Wu, Wai Kit Chan, Xiao Jun Yao, Jing Rong Wang, Liang Liu and Vincent Kam Wai Wong _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:30077-30091. https://doi.org/10.18632/oncotarget.15616

Metrics: PDF 1108 views  |   HTML 1197 views  |   ?  


Abstract

Betty Yuen Kwan Law1, Flora Gordillo-Martínez1, Yuan Qing Qu1, Ni Zhang1, Su Wei Xu1, Paolo Saul Coghi1, Simon Wing Fai Mok1, Jianru Guo1, Wei Zhang1, Elaine Lai Han Leung1, Xing Xing Fan1, An Guo Wu1, Wai Kit Chan1, Xiao Jun Yao1, Jing Rong Wang1, Liang Liu1, Vincent Kam Wai Wong1

1Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China

Correspondence to:

Vincent Kam Wai Wong, email: bowaiwong@gmail.com

Liang Liu, email: lliu@must.edu.mo

Keywords: thalidezine, AMPK activator, autophagy, autophagic cell death, apoptosis-resistant cancer

Received: October 22, 2016     Accepted: January 27, 2017     Published: February 22, 2017

ABSTRACT

Cancers illustrating resistance towards apoptosis is one of the main factors causing clinical failure of conventional chemotherapy. Innovative therapeutic methods which can overcome the non-apoptotic phenotype are needed. The AMP-activated protein kinase (AMPK) is the central regulator of cellular energy homeostasis, metabolism, and autophagy. Our previous study showed that the identified natural AMPK activator is able to overcome apoptosis-resistant cancer via autophagic cell death. Therefore, AMPK is an ideal pharmaceutical target for chemoresistant cancers. Here, we unravelled that the bisbenzylisoquinoline alkaloid thalidezine is a novel direct AMPK activator by using biolayer interferometry analysis and AMPK kinase assays. The quantification of autophagic EGFP-LC3 puncta demonstrated that thalidezine increased autophagic flux in HeLa cancer cells. In addition, metabolic stress assay confirmed that thalidezine altered the energy status of our cellular model. Remarkably, thalidezine-induced autophagic cell death in HeLa or apoptosis-resistant DLD-1 BAX-BAK DKO cancer cells was abolished by addition of autophagy inhibitor (3-MA) and AMPK inhibitor (compound C). The mechanistic role of autophagic cell death in resistant cancer cells was further supported through the genetic removal of autophagic gene7 (Atg7). Overall, thalidezine is a novel AMPK activator which has great potential to be further developed into a safe and effective intervention for apoptosis- or multidrug-resistant cancers.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 15616