Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

Abstract

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.

Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

“…A distinct mechanism has been shown to render cancer cells partially resistant to the suppression of SCD1 activity. The treatment of cancer cells with the SCD1 inhibitor, CVT-11127, caused adenosine monophosphate-activated protein kinase (AMPK) activation via phosphorylation at Thr172, which in turn led to inactivation of the phosphorylation of ACC at Ser79 [78,91]. The carboxylation of acetyl-CoA by ACC generates malonyl-CoA, the substrate for chain elongation in FA biosynthesis [127].…”

“…The carboxylation of acetyl-CoA by ACC generates malonyl-CoA, the substrate for chain elongation in FA biosynthesis [127]. The suppression of FA synthesis in response to SCD1 inhibition has been postulated to protect cells from the excessive accumulation of SFAs, whereas the synthesis of MUFAs is impaired [78,91]. The mechanisms of the lipotoxicity of SFAs and cytoprotective effect of MUFAs were thoroughly discussed by Nolan and Larter [128].…”

“…A similar effect was observed after administration of the FAS inhibitor, GSK2194069, showing that blockade of the FA synthesis cascade contributed to the resistance of cancer cells to SCD1 inhibition. Interestingly, suppressors of autophagy (i.e., STA5326, a Bax channel blocker, vacuolin-1, and hydroxychloroquine) had a synergistic mode of action with T-3764518 (i.e., potentiated its anti-growth activity) in HCT-116 cells [91]. Activated AMPK is a key positive regulator of autophagy [129,130].…”

“…The AMPK-mediated induction of this process has been suggested to provide an escape route from the cytotoxic effects of SCD1 inhibition. The perturbation of FA synthesis and induction of autophagy guarantee, to some extent, the survival of SCD1-knockout HCT-116 cells [91]. These observations led to the conclusion that anticancer therapeutic strategies that consist of SCD1 inhibition may be potentiated by combination therapy that targets AMPK-dependent pathways.…”

Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells

“…To date, several studies have shown that SCD1 deficiency triggers activation of the AMPK signaling pathway in the liver [ 48 ], skeletal muscles [ 20 ], and cancer cell lines [ 49 , 50 ]. The AMPK-mediated actions of SCD1 also include autophagy-dependent cell growth and death [ 49 , 50 ], FA β-oxidation [ 48 ], and histone acetylation [ 20 ]. Consistent with previous studies of other tissues, we found that the loss of SCD1 expression activated AMPK in pancreatic islets and INS-1E cells.…”