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

نویسندگان

  • Betty Yuen Kwan Law
  • Flora Gordillo-Martínez
  • 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
  • Vincent Kam Wai Wong
چکیده

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.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017