Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation

Eun Jin Yun, Chun Jung Lin, Andrew Dang, Elizabeth Hernandez, Jiaming Guo, Wei Min Chen, Joyce Allison, Nathan Kim, Payal Kapur, James B Brugarolas, Kaijie Wu, Dalin He, Chih Ho Lai, Ho Lin, Debabrata Saha, Seung Tae Baek, Ping-chi B Chen, Jer-Tsong Hsieh

Research output: Contribution to journalArticle

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 patient-derived 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 RCC xenograft model or PDX model. Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.

Original languageEnglish (US)
Pages (from-to)4542-4551
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number14
DOIs
StatePublished - Jan 1 2019

Fingerprint

Ionizing Radiation
Renal Cell Carcinoma
Down-Regulation
Gene Expression
Heterografts
Proteins
human DAB2 protein
Ubiquitin-Protein Ligases
Ubiquitination
Radiation Tolerance
Immunoprecipitation
Mass Spectrometry
Research Design
Radiotherapy
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cell Line
Polymerase Chain Reaction
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation. / Yun, Eun Jin; Lin, Chun Jung; Dang, Andrew; Hernandez, Elizabeth; Guo, Jiaming; Chen, Wei Min; Allison, Joyce; Kim, Nathan; Kapur, Payal; Brugarolas, James B; Wu, Kaijie; He, Dalin; Lai, Chih Ho; Lin, Ho; Saha, Debabrata; Baek, Seung Tae; Chen, Ping-chi B; Hsieh, Jer-Tsong.

In: Clinical Cancer Research, Vol. 25, No. 14, 01.01.2019, p. 4542-4551.

Research output: Contribution to journalArticle

Yun, EJ, Lin, CJ, Dang, A, Hernandez, E, Guo, J, Chen, WM, Allison, J, Kim, N, Kapur, P, Brugarolas, JB, Wu, K, He, D, Lai, CH, Lin, H, Saha, D, Baek, ST, Chen, PB & Hsieh, J-T 2019, 'Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation', Clinical Cancer Research, vol. 25, no. 14, pp. 4542-4551. https://doi.org/10.1158/1078-0432.CCR-18-3004
Yun, Eun Jin ; Lin, Chun Jung ; Dang, Andrew ; Hernandez, Elizabeth ; Guo, Jiaming ; Chen, Wei Min ; Allison, Joyce ; Kim, Nathan ; Kapur, Payal ; Brugarolas, James B ; Wu, Kaijie ; He, Dalin ; Lai, Chih Ho ; Lin, Ho ; Saha, Debabrata ; Baek, Seung Tae ; Chen, Ping-chi B ; Hsieh, Jer-Tsong. / Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 14. pp. 4542-4551.
@article{f15c7a83a7154973a63b6b7570b5b400,
title = "Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation",
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 patient-derived 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 RCC xenograft model or PDX model. Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.",
author = "Yun, {Eun Jin} and Lin, {Chun Jung} and Andrew Dang and Elizabeth Hernandez and Jiaming Guo and Chen, {Wei Min} and Joyce Allison and Nathan Kim and Payal Kapur and Brugarolas, {James B} and Kaijie Wu and Dalin He and Lai, {Chih Ho} and Ho Lin and Debabrata Saha and Baek, {Seung Tae} and Chen, {Ping-chi B} and Jer-Tsong Hsieh",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-18-3004",
language = "English (US)",
volume = "25",
pages = "4542--4551",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Downregulation of human DAB2IP gene expression in renal cell carcinoma results in resistance to ionizing radiation

AU - Yun, Eun Jin

AU - Lin, Chun Jung

AU - Dang, Andrew

AU - Hernandez, Elizabeth

AU - Guo, Jiaming

AU - Chen, Wei Min

AU - Allison, Joyce

AU - Kim, Nathan

AU - Kapur, Payal

AU - Brugarolas, James B

AU - Wu, Kaijie

AU - He, Dalin

AU - Lai, Chih Ho

AU - Lin, Ho

AU - Saha, Debabrata

AU - Baek, Seung Tae

AU - Chen, Ping-chi B

AU - Hsieh, Jer-Tsong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 patient-derived 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 RCC xenograft model or PDX model. Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.

AB - 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 patient-derived 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 RCC xenograft model or PDX model. Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.

UR - http://www.scopus.com/inward/record.url?scp=85069055212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069055212&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-3004

DO - 10.1158/1078-0432.CCR-18-3004

M3 - Article

C2 - 31000589

AN - SCOPUS:85069055212

VL - 25

SP - 4542

EP - 4551

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14

ER -