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Cancer Lett. 2018 Nov 28;437:1-12. doi: 10.1016/j.canlet.2018.08.014. Epub 2018 Aug 24.

Integrated proteomic and phosphoproteomic analyses of cisplatin-sensitive and resistant bladder cancer cells reveal CDK2 network as a key therapeutic target.

Author information

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.

KEYWORDS:

Biological network; Bladder cancer; Cisplatin resistance; Competing interests; Global proteome; Phosphoproteomics

PMID:
30145203
PMCID:
PMC6181132
[Available on 2019-11-28]
DOI:
10.1016/j.canlet.2018.08.014

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