Open AccessFeedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition
Author(s) -
Akito Ono,
Osamu Sano,
Ken-ichi Kazetani,
Takamichi Muraki,
Kiyoshi Imamura,
Hiroyuki Sumi,
Junji Matsui,
Hidehisa Iwata
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0181243
Subject(s) - autophagy , ampk , chemistry , cell growth , microbiology and biotechnology , mechanism of action , growth inhibition , cancer cell , cancer research , phosphorylation , biochemistry , biology , cancer , apoptosis , in vitro , protein kinase a , genetics
Elucidating the bioactive compound modes of action is crucial for increasing success rates in drug development. For anticancer drugs, defining effective drug combinations that overcome resistance improves therapeutic efficacy. Herein, by using a biologically annotated compound library, we performed a large-scale combination screening with Stearoyl-CoA desaturase-1 (SCD1) inhibitor, T-3764518, which partially inhibits colorectal cancer cell proliferation. T-3764518 induced phosphorylation and activation of AMPK in HCT-116 cells, which led to blockade of downstream fatty acid synthesis and acceleration of autophagy. Attenuation of fatty acid synthesis by small molecules suppressed the growth inhibitory effect of T-3764518. In contrast, combination of T-3764518 with autophagy flux inhibitors synergistically inhibited cellular proliferation. Experiments using SCD1 knock-out cells validated the results obtained with T-3764518. The results of our study indicated that activation of autophagy serves as a survival signal when SCD1 is inhibited in HCT-116 cells. Furthermore, these findings suggest that combining SCD1 inhibitor with autophagy inhibitors is a promising anticancer therapy.