Abstract 3532: Compound Tc inhibits ATG4 to attenuate autophagic flux and sensitize cancer cells to chemotherapy

Abstract

Abstract Autophagy is induced to protect cancer cells against stresses, including starvation, hypoxia and chemotherapy. Antimalarial drugs chloroquine and its derivative hydroxychloroquine are used to inhibit autophagy and being investigated with clinical trials for certain types of cancer. However, the tumor suppressive effects of the drugs might be autophagy independent, which require more specific inhibitors target autophagy components for clinical uses. Here, we screened FDA-approved drug library with both biochemical and cellular ATG4 reporter assays and found compound Tc blocked proteolysis activity of ATG4, essential proteases in autophagy machinery. Docking and MD simulation results appeared compound Tc was directly associated with active site of ATG4. Further, compound Tc obstructed the binding between ATG4 and MAP1LC3 and accumulated autophagosomes, which in turn reduce autophagic flux in cells. Moreover, compound Tc suppressed tumor viability and sensitized chemotherapy efficacy in two-dimensional and sphere culture model. Silencing ATG4 or overexpression of ATG4 catalytic mutant had no additional effects on tumor suppression compared to compound Tc alone, indicating compound Tc inhibited ATG4s activity to diminish tumor viability. In addition, compound Tc enhanced genotoxic stress-induced apoptosis to synergize chemotherapy efficacy in vitro and in vivo. Thus, we report that the clinical drug compound Tc is a potent ATG4 inhibitor, which could interrogate the role of autophagy in clinical setting and provide compound Tc as an anticancer drug or chemosensitizer. Citation Format: Chih-Wen Shu. Compound Tc inhibits ATG4 to attenuate autophagic flux and sensitize cancer cells to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3532.