Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening

Shao，Fangyuan1,2; Lyu，Xueying1,2; Miao，Kai1,2; Xie，Lisi1; Wang，Haitao1; Xiao，Hao3; Li，Jie1,2; Chen，Qiang1,2; Ding，Renbo1,2; Chen，Ping1,2; Xing，Fuqiang1,4; Zhang，Xu1,2; Luo，Guang Hui5; Zhu，Wenli5; Cheng，Gregory1; Lon，Ng Wai6; Martin，Scott E.7; Wang，Guanyu4; Chen，Guokai1,2; Dai，Yunlu1,2; Deng，Chu Xia1,2

2020

10.1002/advs.202001914

Advanced Science   影响因子和分区

2198-3844

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.

broad drug resistance caspase 3 activation patient-derived organoid proteolysis RNAi screening

SCI ; EI

英语

其他

Chair Professor Grant[CPG 2017-00016-FHS] ; Multi-Year Research Grant (MYRG)[2016-00139-FHS][MYRG2016-00132-FHS][MYRG2017-00113-FHS] ; Science and Technology Development Fund, Macau SAR[094/2015/A3][048/2019/A1][0011/2019/AKP]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:000578427300001

WILEY

20204209341370

Chemical activation ; Diseases ; Proteins ; Drug interactions ; Mitochondria

Biological Materials and Tissue Engineering:461.2 ; Medicine and Pharmacology:461.6 ; Chemical Reactions:802.2 ; Chemical Products Generally:804 ; Organic Compounds:804.1

2-s2.0-85092321504

Scopus

1.Cancer Center,Faculty of Health Sciences,University of Macau,999078,Macao
2.Center for Precision Medicine Research and Training,Faculty of Health Sciences,University of Macau,999078,Macao
3.Guangdong Key Laboratory of Animal Breeding and Nutrition,Institute of Animal Science,Guangdong Academy of Agricultural Sciences,Guangzhou,510640,China
4.Department of Biology,Southern University of Science and Technology,Shenzhen,518055,China
5.Kiang Wu Hospital,820002,Macao
6.Centro Hospitalar Conde de S. Januário,820004,Macao
7.Division of Pre-Clinical Innovation,National Center for Advancing Translational Sciences (NCATS),National Institutes of Health,Bethesda,20892,United States

Shao，Fangyuan,Lyu，Xueying,Miao，Kai,et al. Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening[J]. Advanced Science,2020,7(23).

Shao，Fangyuan.,Lyu，Xueying.,Miao，Kai.,Xie，Lisi.,Wang，Haitao.,...&Deng，Chu Xia.(2020).Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening.Advanced Science,7(23).

Shao，Fangyuan,et al."Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening".Advanced Science 7.23(2020).