AIM: Chemotherapy-induced reactive oxygen species (ROS) not only contribute to apoptosis, but also trigger autophagy. Since autophagy is reported to protect cancer cells from apoptosis, this weakens the therapeutic effect of chemotherapy. This study aimed at identifying the key molecules that determine the cellular response to ROS and, therefore, provide better strategies to increase chemotherapeutic efficiency. RESULTS: Increasing concentrations of N-(4-hydroxyphenyl) retinamide (4-HPR)-treatment pushed autophagy down to apoptosis in a dose-dependent manner, and 4-HPR-induced ROS contribute to this process. Since we found that ASK1-regulated JNK1 and p38 are responsible for 4-HPR-induced autophagy and apoptosis, respectively, we further utilized co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry analysis to identify proteins that specifically bind to ASK1 under different oxidative states. Of note, DJ-1, a crucial antioxidant protein, was identified. Interestingly, DJ-1 functions as a redox sensor that senses ROS levels and determines the cellular response to 4-HPR: Under mild oxidative stress, moderate oxidation of DJ-1 is recruited to inhibit the activity of ASK1 and maintain cell viability by activating autophagy; under a lethal level of oxidative stress, excessive oxidized DJ-1 dissociates from ASK1 and activates it, thereby initiating p38 activation and enabling the cells to commit to apoptosis. Moreover, the depletion of DJ-1 increases the sensitivity of tumor cells to 4-HPR both in vitro and in vivo. INNOVATION: Our results reveal that the different oxidation states of DJ-1 function as a cellular redox sensor of ROS caused by 4-HPR and determine the cell fate of autophagy or apoptosis. Moreover, the results suggest that DJ-1 might be a potent therapeutic target for cancer treatment. CONCLUSION: ROS-mediated changes in the oxidation state of DJ-1 are involved in 4-HPR's effect on pushing autophagy down to apoptosis. Consequently, this change mediates ASK1 activation by regulating DJ-1-ASK1 complex formation and determines the cell fate of autophagy or apoptosis.
AIM: Chemotherapy-induced reactive oxygen species (ROS) not only contribute to apoptosis, but also trigger autophagy. Since autophagy is reported to protect cancer cells from apoptosis, this weakens the therapeutic effect of chemotherapy. This study aimed at identifying the key molecules that determine the cellular response to ROS and, therefore, provide better strategies to increase chemotherapeutic efficiency. RESULTS: Increasing concentrations of N-(4-hydroxyphenyl) retinamide (4-HPR)-treatment pushed autophagy down to apoptosis in a dose-dependent manner, and 4-HPR-induced ROS contribute to this process. Since we found that ASK1-regulated JNK1 and p38 are responsible for 4-HPR-induced autophagy and apoptosis, respectively, we further utilized co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry analysis to identify proteins that specifically bind to ASK1 under different oxidative states. Of note, DJ-1, a crucial antioxidant protein, was identified. Interestingly, DJ-1 functions as a redox sensor that senses ROS levels and determines the cellular response to 4-HPR: Under mild oxidative stress, moderate oxidation of DJ-1 is recruited to inhibit the activity of ASK1 and maintain cell viability by activating autophagy; under a lethal level of oxidative stress, excessive oxidized DJ-1 dissociates from ASK1 and activates it, thereby initiating p38 activation and enabling the cells to commit to apoptosis. Moreover, the depletion of DJ-1 increases the sensitivity of tumor cells to 4-HPR both in vitro and in vivo. INNOVATION: Our results reveal that the different oxidation states of DJ-1 function as a cellular redox sensor of ROS caused by 4-HPR and determine the cell fate of autophagy or apoptosis. Moreover, the results suggest that DJ-1 might be a potent therapeutic target for cancer treatment. CONCLUSION:ROS-mediated changes in the oxidation state of DJ-1 are involved in 4-HPR's effect on pushing autophagy down to apoptosis. Consequently, this change mediates ASK1 activation by regulating DJ-1-ASK1 complex formation and determines the cell fate of autophagy or apoptosis.
Authors: Jin Xu; Nan Zhong; Haoyong Wang; Joshua E Elias; Christina Y Kim; Irina Woldman; Christian Pifl; Steven P Gygi; Changiz Geula; Bruce A Yankner Journal: Hum Mol Genet Date: 2005-03-24 Impact factor: 6.150
Authors: Anita L Sabichi; Seth P Lerner; E Neely Atkinson; H Barton Grossman; Nancy P Caraway; Colin P Dinney; David F Penson; Surena Matin; Ashish Kamat; Louis L Pisters; Daniel W Lin; Ruth L Katz; Dean E Brenner; George P Hemstreet; Mary Wargo; Archie Bleyer; William H Sanders; John L Clifford; Howard L Parnes; Scott M Lippman Journal: Clin Cancer Res Date: 2008-01-01 Impact factor: 12.531
Authors: Javier Egea; Isabel Fabregat; Yves M Frapart; Pietro Ghezzi; Agnes Görlach; Thomas Kietzmann; Kateryna Kubaichuk; Ulla G Knaus; Manuela G Lopez; Gloria Olaso-Gonzalez; Andreas Petry; Rainer Schulz; Jose Vina; Paul Winyard; Kahina Abbas; Opeyemi S Ademowo; Catarina B Afonso; Ioanna Andreadou; Haike Antelmann; Fernando Antunes; Mutay Aslan; Markus M Bachschmid; Rui M Barbosa; Vsevolod Belousov; Carsten Berndt; David Bernlohr; Esther Bertrán; Alberto Bindoli; Serge P Bottari; Paula M Brito; Guia Carrara; Ana I Casas; Afroditi Chatzi; Niki Chondrogianni; Marcus Conrad; Marcus S Cooke; João G Costa; Antonio Cuadrado; Pham My-Chan Dang; Barbara De Smet; Bilge Debelec-Butuner; Irundika H K Dias; Joe Dan Dunn; Amanda J Edson; Mariam El Assar; Jamel El-Benna; Péter Ferdinandy; Ana S Fernandes; Kari E Fladmark; Ulrich Förstermann; Rashid Giniatullin; Zoltán Giricz; Anikó Görbe; Helen Griffiths; Vaclav Hampl; Alina Hanf; Jan Herget; Pablo Hernansanz-Agustín; Melanie Hillion; Jingjing Huang; Serap Ilikay; Pidder Jansen-Dürr; Vincent Jaquet; Jaap A Joles; Balaraman Kalyanaraman; Danylo Kaminskyy; Mahsa Karbaschi; Marina Kleanthous; Lars-Oliver Klotz; Bato Korac; Kemal Sami Korkmaz; Rafal Koziel; Damir Kračun; Karl-Heinz Krause; Vladimír Křen; Thomas Krieg; João Laranjinha; Antigone Lazou; Huige Li; Antonio Martínez-Ruiz; Reiko Matsui; Gethin J McBean; Stuart P Meredith; Joris Messens; Verónica Miguel; Yuliya Mikhed; Irina Milisav; Lidija Milković; Antonio Miranda-Vizuete; Miloš Mojović; María Monsalve; Pierre-Alexis Mouthuy; John Mulvey; Thomas Münzel; Vladimir Muzykantov; Isabel T N Nguyen; Matthias Oelze; Nuno G Oliveira; Carlos M Palmeira; Nikoletta Papaevgeniou; Aleksandra Pavićević; Brandán Pedre; Fabienne Peyrot; Marios Phylactides; Gratiela G Pircalabioru; Andrew R Pitt; Henrik E Poulsen; Ignacio Prieto; Maria Pia Rigobello; Natalia Robledinos-Antón; Leocadio Rodríguez-Mañas; Anabela P Rolo; Francis Rousset; Tatjana Ruskovska; Nuno Saraiva; Shlomo Sasson; Katrin Schröder; Khrystyna Semen; Tamara Seredenina; Anastasia Shakirzyanova; Geoffrey L Smith; Thierry Soldati; Bebiana C Sousa; Corinne M Spickett; Ana Stancic; Marie José Stasia; Holger Steinbrenner; Višnja Stepanić; Sebastian Steven; Kostas Tokatlidis; Erkan Tuncay; Belma Turan; Fulvio Ursini; Jan Vacek; Olga Vajnerova; Kateřina Valentová; Frank Van Breusegem; Lokman Varisli; Elizabeth A Veal; A Suha Yalçın; Olha Yelisyeyeva; Neven Žarković; Martina Zatloukalová; Jacek Zielonka; Rhian M Touyz; Andreas Papapetropoulos; Tilman Grune; Santiago Lamas; Harald H H W Schmidt; Fabio Di Lisa; Andreas Daiber Journal: Redox Biol Date: 2017-05-18 Impact factor: 11.799