A novel UCHL 3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair

Zhiwang Song, Xinyi Tu, Qin Zhou, Jinzhou Huang, Yuping Chen, Jiaqi Liu, Seung Baek Lee, Wootae Kim, Somaira Nowsheen, Kuntian Luo, Jian Yuan, Zhenkun Lou

Research output: Contribution to journalArticle

Abstract

Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.

Original languageEnglish (US)
Article number398
JournalCell Death and Disease
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Triple Negative Breast Neoplasms
Double-Stranded DNA Breaks
Homologous Recombination
DNA Damage
Ubiquitination
Therapeutics
Ionizing Radiation
Heterografts
DNA Repair
Radiotherapy
Poly(ADP-ribose) Polymerase Inhibitors
perifosine
Radiation
Drug Therapy
Growth
Neoplasms

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

A novel UCHL 3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair . / Song, Zhiwang; Tu, Xinyi; Zhou, Qin; Huang, Jinzhou; Chen, Yuping; Liu, Jiaqi; Lee, Seung Baek; Kim, Wootae; Nowsheen, Somaira; Luo, Kuntian; Yuan, Jian; Lou, Zhenkun.

In: Cell Death and Disease, Vol. 10, No. 6, 398, 01.06.2019.

Research output: Contribution to journalArticle

Song, Zhiwang ; Tu, Xinyi ; Zhou, Qin ; Huang, Jinzhou ; Chen, Yuping ; Liu, Jiaqi ; Lee, Seung Baek ; Kim, Wootae ; Nowsheen, Somaira ; Luo, Kuntian ; Yuan, Jian ; Lou, Zhenkun. / A novel UCHL 3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair In: Cell Death and Disease. 2019 ; Vol. 10, No. 6.
@article{3038b862694b43afa7b1e44c05a2bd19,
title = "A novel UCHL 3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair",
abstract = "Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.",
author = "Zhiwang Song and Xinyi Tu and Qin Zhou and Jinzhou Huang and Yuping Chen and Jiaqi Liu and Lee, {Seung Baek} and Wootae Kim and Somaira Nowsheen and Kuntian Luo and Jian Yuan and Zhenkun Lou",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41419-019-1628-8",
language = "English (US)",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - A novel UCHL 3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair

AU - Song, Zhiwang

AU - Tu, Xinyi

AU - Zhou, Qin

AU - Huang, Jinzhou

AU - Chen, Yuping

AU - Liu, Jiaqi

AU - Lee, Seung Baek

AU - Kim, Wootae

AU - Nowsheen, Somaira

AU - Luo, Kuntian

AU - Yuan, Jian

AU - Lou, Zhenkun

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.

AB - Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.

UR - http://www.scopus.com/inward/record.url?scp=85065878753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065878753&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-1628-8

DO - 10.1038/s41419-019-1628-8

M3 - Article

C2 - 31113933

AN - SCOPUS:85065878753

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 6

M1 - 398

ER -