Jae Hun Jung1, Sungyong You2, Jae Won Oh1, Junhee Yoon3, Austin Yeon3, Muhammad Shahid3, Eunho Cho4, Vikram Sairam4, Taeeun D Park5, Kwang Pyo Kim6, Jayoung Kim7. 1. Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Republic of Korea. 2. Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 3. Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 4. Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; University of California, Los Angeles, CA, USA. 5. Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; University of California, Berkeley, CA, USA. 6. Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, Republic of Korea. Electronic address: kimkp@khu.ac.kr. 7. Department of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; University of California, Los Angeles, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: Jayoung.Kim@cshs.org.
Abstract
BACKGROUND: Cisplatin-based chemotherapy is currently part of the standard of care for bladder cancer (BC). Unfortunately, some patients respond poorly to chemotherapy and have acquired or developed resistance. The molecular mechanisms underlying this resistance remain unclear. Here, we introduce a multidimensional proteomic analysis of a cisplatin-resistant BC model that provides different levels of protein information, including that of the global proteome and phosphoproteome. METHODS: To characterize the global proteome and phosphoproteome in cisplatin-resistant BC cells, liquid chromatography-mass spectrometry/mass spectrometry experiments combined with comprehensive bioinformatics analysis were performed. Perturbed expression and phosphorylation levels of key kinases associated with cisplatin resistance were further studied using various cell biology assays, including western blot analysis. RESULTS: Analyses of protein expression and phosphorylation identified significantly altered proteins, which were also EGF-dependent and independent. This suggests that protein phosphorylation plays a significant role in cisplatin-resistant BC. Additional network analysis of significantly altered proteins revealed CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. In addition to this, we identified the CDK2 network, which consists of CDK2 and its 5 substrates, as being significantly associated with poor survival after cisplatin chemotherapy. CONCLUSIONS: Collectively, these findings potentially provide a novel way of classifying higher-risk patients and may guide future research in developing therapeutic targets.
BACKGROUND: Cisplatin-based chemotherapy is currently part of the standard of care for bladder cancer (BC). Unfortunately, some patients respond poorly to chemotherapy and have acquired or developed resistance. The molecular mechanisms underlying this resistance remain unclear. Here, we introduce a multidimensional proteomic analysis of a cisplatin-resistant BC model that provides different levels of protein information, including that of the global proteome and phosphoproteome. METHODS: To characterize the global proteome and phosphoproteome in cisplatin-resistant BC cells, liquid chromatography-mass spectrometry/mass spectrometry experiments combined with comprehensive bioinformatics analysis were performed. Perturbed expression and phosphorylation levels of key kinases associated with cisplatin resistance were further studied using various cell biology assays, including western blot analysis. RESULTS: Analyses of protein expression and phosphorylation identified significantly altered proteins, which were also EGF-dependent and independent. This suggests that protein phosphorylation plays a significant role in cisplatin-resistant BC. Additional network analysis of significantly altered proteins revealed CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. In addition to this, we identified the CDK2 network, which consists of CDK2 and its 5 substrates, as being significantly associated with poor survival after cisplatin chemotherapy. CONCLUSIONS: Collectively, these findings potentially provide a novel way of classifying higher-risk patients and may guide future research in developing therapeutic targets.
Authors: A Gordon Robertson; Jaegil Kim; Hikmat Al-Ahmadie; Joaquim Bellmunt; Guangwu Guo; Andrew D Cherniack; Toshinori Hinoue; Peter W Laird; Katherine A Hoadley; Rehan Akbani; Mauro A A Castro; Ewan A Gibb; Rupa S Kanchi; Dmitry A Gordenin; Sachet A Shukla; Francisco Sanchez-Vega; Donna E Hansel; Bogdan A Czerniak; Victor E Reuter; Xiaoping Su; Benilton de Sa Carvalho; Vinicius S Chagas; Karen L Mungall; Sara Sadeghi; Chandra Sekhar Pedamallu; Yiling Lu; Leszek J Klimczak; Jiexin Zhang; Caleb Choo; Akinyemi I Ojesina; Susan Bullman; Kristen M Leraas; Tara M Lichtenberg; Catherine J Wu; Nicholaus Schultz; Gad Getz; Matthew Meyerson; Gordon B Mills; David J McConkey; John N Weinstein; David J Kwiatkowski; Seth P Lerner Journal: Cell Date: 2017-10-05 Impact factor: 41.582
Authors: Muhammad Shahid; Min Young Lee; Honit Piplani; Allen M Andres; Bo Zhou; Austin Yeon; Minjung Kim; Hyung L Kim; Jayoung Kim Journal: Cell Cycle Date: 2018-12-17 Impact factor: 5.173
Authors: Jochen Rutz; Sebastian Maxeiner; Timothy Grein; Marlon Sonnenburg; Salma El Khadir; Nino Makhatelashvili; Johanna Mann; Hui Xie; Jindrich Cinatl; Anita Thomas; Felix K-H Chun; Axel Haferkamp; Roman A Blaheta; Igor Tsaur Journal: Int J Mol Sci Date: 2022-09-20 Impact factor: 6.208