Cbl-b-dependent degradation of FLIPL is involved in ATO-induced autophagy in leukemic K562 and gastric cancer cells

• Published in: FEBS letters Vol. 586; no. 19; pp. 3104 - 3110
• Main Authors: Zhang, Guodong, Liu, Jing, Zhang, Ye, Qu, Jinglei, Xu, Ling, Zheng, Huachuan, Liu, Yunpeng, Qu, Xiujuan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 21.09.2012
• Subjects: Arsenic trioxide; ATO; Autophagy; casitas B-lineage lymphoma-b; Cbl-b; chlorochine; FAK; FLICE-like inhibitory protein long; FLICE-like inhibitory protein short; FLIPL; FLIPS; focal adhesion kinase; TNF; tumor necrosis factor; FLIPL; FAK; FLIPS; Arsenic trioxide; ATO; Cbl-b; TNF; Autophagy; CQ
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2012.07.067

► FLIPL is a critical regulator of ATO-induced autophagy in K562 and MGC803 cells. ► Degradation of FLIPL protein by ATO is mediated through the ubiquitin–proteasome pathway. ► Cbl-b is involved in ATO-induced ubiquitination of FLIPL in K562 and MGC803 cells. Various molecular mechanisms are involved in the efficacy of arsenic trioxide (ATO) against malignant hematologic and some solid tumors. FLICE-like inhibitory protein (FLIP) is an inhibitor of apoptosis mediated by death receptors. In this study, we identified a new link between the down-regulation of cellular FLIPL and ATO-induced autophagy. ATO induced the degradation of FLIPL in K562 and MGC803 cells, which was mediated by the ubiquitin–proteasome pathway. Moreover, the casitas B-lineage lymphoma-b (Cbl-b) was involved in this process, which interacted with FLIPL and promoted proteasomal degradation of FLIPL. Our findings lead to a better understanding of the mechanism of action of ATO, and suggest that a novel signaling pathway is required for ATO-induced autophagy in K562 and MGC803 cells. FLIP-Lphysically interacts with CBL-B by anti bait coimmunoprecipitation (View interaction)