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Abstract
Ubiquitin–proteasome system (UPS) and autophagy–lysosome pathway (ALP) are two major systems for protein quality control (PQC) in eukaryotic cells. Interconnectivity between these two pathways has been suggested, but the molecular detail of how they impact each other remains elusive. Proteasomal deubiquitinase (DUB) is an important constituent in the UPS and has proved to be a novel anticancer target. We have previously found that a novel DUB inhibitor, nickel complex NiPT, induces apoptosis in both cultured tumor cell lines and cancer cells from acute myeloid leukemia human patients. In this study, we found that NiPT triggered autophagy both in vitro and in vivo. Mechanistically, NiPT targets two DUBs, USP14, and UCHL5, and increased the total cellular level of polyubiquitination. Deletion of the Ubiquitin Associated (UBA) domain of P62 that is required for polyubiquitin binding prevented NiPT-induced autophagy. NiPT-induced autophagy is through either concomitant activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) signaling, or eliciting endoplasmic reticulum (ER)-stress by activating activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Moreover, NiPT could induce more lung cancer cells undergoing apoptosis if it synergistically uses autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cell from death. Collectively, our findings demonstrate that autophagy inhibition enhances the anticancer effects of proteasomal DUB inhibitor and might be an effective treatment strategy for lung cancer.
Highlights
Ubiquitin–proteasome system (UPS) is the main proteolytic pathway for short-lived, misfolded, and damaged proteins in cells, and are involved in the degradation of more than 80% of proteins in cells [1, 2]
As p62 has a ubiquitin-binding domain (UBA), which may contribute to the ubiquitin accumulation upon inhibition of the DUBs, we examined if the deletion of the Ubiquitin Associated (UBA) domain will affect the autophagy induced by NiPT
We synthesized a number of metal complexes and applied them to lung cancer cells
Summary
Ubiquitin–proteasome system (UPS) is the main proteolytic pathway for short-lived, misfolded, and damaged proteins in cells, and are involved in the degradation of more than 80% of proteins in cells [1, 2]. UPS-mediated protein degradation is a multistep reaction process with a variety of different proteins involved [3]. The protein to be degraded is first labeled by ubiquitin and recognized and degraded by proteasome. Through such a process that requires energy consumption, cells degrade unwanted proteins in a highly specific way [4]. In addition to being a garbage disposal biological machinery, UPS regulates a series of important biological processes. Studies confirmed that UPS has important pathophysiological significance in cardiovascular disease, which can regulate the occurrence and development of important diseases such as atherosclerosis, reperfusion injury after ischemia, familial cardiomyopathy, myocardial hypertrophy, and heart failure [6]
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