Open AccessThalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death
Author(s) -
Betty Yuen Kwan Law,
Flora Gordillo-Martnez,
Yuan Qing Qu,
Zhaohui Ni,
Su Xu,
Paolo Coghi,
Simon Wing Fai Mok,
Junhong Guo,
Wei Zhang,
Elaine Lai Han Leung,
Xing Fan,
An Guo Wu,
Wai Kit Chan,
Yao Xiao,
Jing Rong Wang,
Liang Liu
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.15616
Subject(s) - ampk , autophagy , programmed cell death , apoptosis , cancer cell , activator (genetics) , cancer research , microbiology and biotechnology , hela , protein kinase a , amp activated protein kinase , kinase , biology , chemistry , cell , cancer , biochemistry , genetics , gene
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.