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Downregulation of Human DAB2IP Gene Expression in Renal Cell Carcinoma Results in Resistance to Ionizing Radiation

Title
Downregulation of Human DAB2IP Gene Expression in Renal Cell Carcinoma Results in Resistance to Ionizing Radiation
Authors
BAEK, SEUNG TAEYUN, EUN JINChun-Jung LinAndrew DangElizabeth HernandezJiaming GuoWei-Min ChenJoyce AllisonNathan KimPayal KapurJames BrugarolasKaijie WuDalin HeChih-Ho LaiHo LinDebabrata SahaBenjamin P.C. ChenJer-Tsong Hsieh
Date Issued
15-Jul-2019
Publisher
AMER ASSOC CANCER RESEARCH
Abstract
Purpose: Renal cell carcinoma (RCC) is known to be highly radioresistant but the mechanisms associated with radioresistance have remained elusive. We found DOC-2/DAB2 interactive protein (DAB2IP) frequently downregulated in RCC, is associated with radioresistance. In this study, we investigated the underlying mechanism regulating radioresistance by DAB2IP and developed appropriate treatment. Experimental Design: Several RCC lines with or without DAB2IP expression were irradiated with ionizing radiation (IR) for determining their radiosensitivities based on colony formation assay. To investigate the underlying regulatory mechanism of DAB2IP, immunoprecipitation-mass spectrometry was performed to identify DAB2IP-interactive proteins. PARP-1 expression and enzymatic activity were determined using qRT-PCR, Western blot analysis, and ELISA. In vivo ubiquitination assay was used to test PARP-1 degradation. Furthermore, in vivo mice xenograft model and patientderived xenograft (PDX) model were used to determine the effect of combination therapy to sensitizing tumors to IR. Results: We notice that DAB2IP-deficient RCC cells acquire IR-resistance. Mechanistically, DAB2IP can form a complex with PARP-1 and E3 ligases that is responsible for degrading PARP-1. Indeed, elevated PARP-1 levels are associated with the IR resistance in RCC cells. Furthermore, PARP-1 inhibitor can enhance the IR response of either RCCxenograft model orPDX model. Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IRresistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.
Keywords
EPITHELIAL OVARIAN-CANCER; BRCA MUTATION STATUS; DOUBLE-STRAND BREAKS; POLY(ADP-RIBOSE) POLYMERASE; DNA-DAMAGE; PARP-1; RADIOTHERAPY; INHIBITION; SURVIVAL; OLAPARIB
URI
http://oasis.postech.ac.kr/handle/2014.oak/98898
ISSN
1078-0432
Article Type
Article
Citation
CLINICAL CANCER RESEARCH, vol. 25, no. 14, page. 4542 - 4551, 2019-07-15
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 BAEK, SEUNG TAE
Div of Integrative Biosci & Biotech
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