High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

Autor: Jeong A. Hong, Soo Jin Choi, Zhezhu Han, Geun-Hyeok Oh, Yeonsoo Joo, Hye Jin Choi, Ji Hyun Lee, Jae J. Song, Suwan Ko, Rong Xu
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Experimental and Molecular Medicine, Vol 51, Iss 10, Pp 1-20 (2019)
Experimental & Molecular Medicine
ISSN: 2092-6413
1226-3613
Popis: When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.
Cancer: Using viruses as therapy Cancer therapies that use a virus to kill tumor cells may get a boost by suppressing a common, ubiquitously expressed protein called Daxx. The relatively new field of virotherapy uses engineered adenoviruses, which usually cause fevers, coughs, or sore throats, to attack tumor cells, enabling treatment of advanced stage cancers, or those that have spread through the body. However, the immune system can attack the therapeutic virus, preventing it from replicating and reducing its effectiveness. Hye Jin Choi and Jae Song at Yonsei University, Seoul, South Korea, and coworkers have been investigating ways to maximize replication of the therapeutic virus. They found that suppressing Daxx improved viral replication; further testing showed that suppressing Daxx acted via different mechanisms in mouse and human cancer cells. These results will help develop more effective virus-based cancer therapies.
Databáze: OpenAIRE
Externí odkaz: